The second manuscript summarizes the magical medicinal importance of the Ammannia spp. The third manuscript emphasizes the role of ATP-binding cassette ABC transporters in neurodegenerative diseases and significance of botanicals as modulators of ABC transporters . The fourth manuscript provides the up-to-date summary on antifungals from plant and marine sources which can be realized by combinatorial studies along with standard anti-fungals . The fifth manuscript describes the recent advancements and historical developments observed during the past 42 years focusing mainly on important ventures of the antimalarial 1,2,4-trioxolanes ozonides .
The sixth review encompasses the most important secondary metabolites of plants i. The last review encompasses the development of resistance by carbapenemase and drug transporters as important targets for pharmacokinetic studies . This review also explores wide variety of botanicals as their probable inhibitors . Last but not the least our sincere gratitude for the support by all who were directly or indirectly helped us to make this issue a success.
We specially thank Dr. We owe utmost gratitude towards referees and the authors. Without their help, we could not have such a good thematic issue. Further, development of resistance against the frontline anti-tubercular drugs has worsened the already alarming situation. The four inexpensive and effective first lines anti TB drugs ethambutol, isoniazid, rifampicin and pyrazinamide were established nearly fifty years ago. Although during this period many active compounds underwent clinical trials, but none of them could get US-FDA approval.
Therefore, there is an urgent need of intensive drug discovery to develop new, more effective, affordable and accessible anti-tubercular agents possessing novel modes of action, which could reduce the time and burden of all kind of drug resistant TB. In order to control tuberculosis, there is a urgent need to develop novel and more efficient drugs. In this context, targeting the pathogen virulence factors, and particularly signal mechanisms, seems to be a promising approach.
By contrast PknG and PknH are involved in Mtb virulence and adaptation, and are fundamental for the pathogen growth in infection models. In this review Prof. Chiarelli has presented and discussed the principal inhibitors of the mycobacterial STPKs. In particular, medicinal chemistry efforts have been focused on discovering new antimycobacterial compounds, targeting three of these kinases, namely PknA, PknB and PknG demonstrating that targeting Mtb STPKs could be a new promising strategy for the development of drugs to treat TB infections .
Hispolons are natural products and recently anti TB activity in these compounds have been reported. In this research article Prof. Muthyala Murali Krishna Kumar and his co-workers tried to optimize the structure with bioisosteric replacement of 1,3- diketo functional group with the corresponding pyrazole and isoxazole moieties. They prepared a total of 44 compounds and screened for anti TB activity and antibacterial activity.
Among all two compounds showed highest potency with MIC 1. Further, they concluded that computational studies and in vitro screening results are indicating at mtFabH as the probable target for these compounds . Some time ago Prof. Among all, three compounds showed the highest activity. All compounds were tested against three cancer cell lines and showed low cytotoxicity. Among the three one compound was the most potent against resistant and sensitive Mycobacterium tuberculosis in this series with important information and perspectives in the search of new bioactive compounds based on Mefloquine analogs .
Therefore, there is an urgent need of intensive drug discovery to develop new, more effective, affordable and accessible anti-tubercular agents possessing novel modes of action, which could reduce the time and burden of drug resistant TB. The recent years have witnessed 4H-1,3-benzothiazinone as a promising class of antimycobacterial agents specially against resistance TB strain. In this regard Prof. DNA gyrase is a clinically validated drug target, currently targeted only by fluoroquinolones class of antibacterials.
But in order to treat serious infections, including multi-drug resistant tuberculosis fluoroquinolones are increasingly being overutilized. This increases the probability of resistance to fluoroquinolones, which is mediated by a single amino acid change in gyrA, leading to class wide resistance. The third article of this issue by Dr. Sidharth Chopra and his group provide an overview on the recent progress in identifying novel scaffolds which target DNA gyrase and provide an update on their discovery and development status .
Therefore, DHA derivatives have potential for anti-tubercular drug development from an inexpensive and non-toxic natural product . Isocitrate lyase MtbICL , a key enzyme of glyoxylate pathway has been shown to be involved in the persistence, is an attractive drug target against persistent mycobacteria. In this regard, Dr. Ashok Sharma and his group have integrated virtual screening, which resulted in the identification of shinjudilactone quassinoid , lecheronol A pimarane and caniojane diterpene as potential MtbICL inhibitors .
Tryptanthrin is a known inhibitor of Mtb enoyl-acyl carrier protein reductase InhA. In this regard, Prof. Macaev and his group members modified the structure of tryptanthrin in such a way that it gave a group of 5H-[1,3,4] thiadiazolo [2,3- b]quinazolinone analogues with varying degree of antimycobacterial activity. He also carried out molecular modeling studies to investigate the binding mechanisms of the synthesized ligands with InhA . It is known that several imidazole and 1, 2, 4-triazole derivatives possess both antimycobacterial and antifungal activity.
Keeping this thing in mind Prof. Daniele Zampieri and his group members synthesized some 1- 1- aryl 2, 6-dichlorophenyl hydrazono ethyl-1H-imidazole and 1H-1,2,4-triazole derivatives and evaluated their antitubercular activity. Among the series two derivatives showed most promising activity and, according to the docking assessment, the compounds could be CYP51 inhibitors . In an earlier communication Dr. Srivastava and his group members for the first time reported anti-tubercular activity in dihydroartemisinin DHA-1 against Mtb H37Rv, which prompted him to carry out chemical transformation of DHA into various derivatives and study their antitubercular potential.
Thus, as a part of their drug discovery program in this research article they semi-synthetically converted DHA into four new acyl derivatives and in-vitro evaluated their anti-tubercular potential against Mycobacterium tuberculosis H37Rv virulent strain. Two out of the four derivatives showed MIC Additionally, it showed no cytotoxicity towards the Vero C cells and Mouse bone marrow derived macrophages. Since, dihydroartemisinin is widely used as an antimalarial drug; these results may be of great help in anti-tubercular drug development from a very common, inexpensive, and non toxic natural product .
Modern drug discovery has now become largely target-based, where attempts are made to find chemical agents that can hit the disease-specific enzymes or pathways. Several biological processes, such as cell growth, DNA replication, transcriptional activation, transmembrane signal transduction, etc. Thus two issues of this journal have been devoted to highlighting the roles of PPIs. In second article, Cicaloni et al. Several approaches, models and methods from graph theory are applied to PPIs in order to reveal hidden properties and features of an intricate network of proteins.
Network profiling together with the extraction of knowledge is crucial to better understand the biological significance of PPIs . PDEs are proteins which do not operate alone but in complexes made up of a large number of proteins which bind to each other via protein-protein interactions .
These three articles have highlighted the roles of PPIs in drug development and might be of great interest to those involved in biochemical and pharmaceutical research. I have equally enjoyed reading these three articles too and hope so will also the readers. In this context, protein-protein interactions PPIs have emerged an interesting class of targets. It has been now well understood that various human diseases are associated with aberrant protein-protein interactions. Among them the notable ones are cervical cancer, leukemia, bacterial infections, inflammation, diabetes, osteoporosis, and neurodegenerative diseases.
Consequently, over the last decades, protein-protein interactions have developed into attractive molecular targets for the discovery of potential drugs. Thus, drug design targeting PPIs is a burning area and the present two thematic issues on it present some very interesting articles covering some important aspects of this area.
Protein-protein interactions are of crucial importance in regulating the biological processes of cells, both in normal and diseased conditions. Recently, significant progress has been made in targeting PPIs using small molecules and achieving promising results . Kinases are key modulators in regulating diverse range of cellular activities and are an essential part of the protein-protein interactome . I have greatly enjoyed reading all these articles and hope so will do the readers and find them useful for further research on protein-protein interactions.
This issue is related to current trends in enzyme inhibition and activation in drug design. The topics which are presented deal with prediction of drug-drug interactions, as well as enzymes involved in tuberculosis, IMPDH enzymes, antimicrobial activity of thiazole-based chalcones and PTP1B inhibitory action and anti-diabetic properties. The first paper deals with prediction of drug-drug interactions DDIs related to inhibition or induction of drug-metabolizing enzymes. In this review, in silico methods that may be applied for prediction of inhibition or induction of DMEs are summarized and appropriate computational methods are described for DDI prediction, showing the current place and perspectives of these approaches in medicinal and pharmaceutical chemistry.
Sources of information on DDIs that can be used in pharmaceutical investigations, medicinal practice and computational models creation are explained in detail and the problem of inaccuracy and redundancy of this data is discussed. The methods of computer-aided prediction of DDI including the state-of-the-art in physiologically based pharmacokinetic PBPK computational approaches and in protein-based in silico methods dealing with DMEs is provided.
In the section of ligand-based methods is described utilization of pharmacophore models, molecular field analysis, quantitative structure-activity relationships QSAR , and similarity analysis applied to prediction of DDIs related to inhibition or induction of DMEs. Also the problem of DDI severity assessment is addressed highlighting the issues, perspectives and practical use of in silico methods is discussed . The next paper deals with Mycobacterial tuberculosis enzymes. A literature search has been carried out to find the different chemical molecules including drugs and their enzyme targets responsible for their antitubercular activities in recent years.
The major focus has been on the new target ATP synthase. Such an attempt may be useful in designing of new screening using the Asinex database considering the important three sub-structures of bedaquiline TMC containing quinoline, tertiary amine and hydroxyl functionality identifying amodiaquin to have these features but with no antitubercular activity. These studies were followed by molecular docking using a homology model of mycobacterial ATP synthase and a set of 18 novel substituted chloroquinolines, belonging to the 2-methylsubstituted aminochloroquinolines. This compound library was designed , synthesized and screened against Mycobacterium smegmatis ATP synthase; 6 compounds with the lowest inhibitory concentration IC50 values 0.
A variety of different compounds such as benzo[d]oxazol-2 3h -ones derivatives, pyrrolidinone and pyrrolidines, tetrahydropyrans, methylthiazoles and many others were synthesized and evaluated against InhA, enzymes involved in the synthesis of mycobacterial cell walls . Another paper is dedicated to design, synthesis, evaluation of antimicrobial activity and molecular docking study of new thiazole-based chalcones.
The designed compounds were synthesized using classical methods of organic synthesis. The in vivo evaluation of antimicrobial activity was performed by microdilution method. All 28 tested compounds were active showing in some cases better activity than ampicillin and streptomycin, and all compounds were much more potent than ketoconazole and bifonazole . Helicobacter pylori infection is one of the primary causes of peptic ulcer followed by gastric cancer in the world population.
Taking into account increased occurrences of multi-drug resistance to the currently available antibiotics, there is an urgent need for a new class of drugs against H. Several lead molecules which could help in a further endeavor toward identifying selective and potent inhibitors of the Hp IMPDH to fight multi-drug resistance in H. The last paper is dealing with docking assisted prediction and biological evaluation of Sideritis L.
Sideritis L. Lamiaceae is a herbal plant growing around the Mediterranean sea which has been included in the Mediterranean diet for centuries. The antioxidant and anti-inflammatory activity of the components of Sideritis L. Docking prediction was performed and the components of Sideritis L. Four of the five tested components exhibited inhibitory action. Both an acetoside and lavandulfolioside showed the best activity with IC50 values of 4. The topics which are presented deal with inhibitors of PTP1B, PDE5A, Alzheimer disease, xenobiotic metabolizing enzymes as well as caffeic acid derivatives as antimicrobial agents.
The first paper show the attempts made in developing of Protein Tyrosine Phosphatase PTP1B inhibitors with high potency, selectivity and bioavailability and sum up the indications for favorable structural characteristics of effective PTP1B inhibitors. The research for finding PTP1B inhibitors started with the design of molecules mimicking the tyrosine substrate of the enzyme and revealed the main requirements for small inhibitors binding to the active site surrounding Cys Permanent inhibition of the enzyme by oxidation of the catalytic Cys is also highlighted.
Moreover, covalent modification of Cys, placed near but not inside the catalytic pocket, has been associated with permanent inhibition of the enzyme . The next review refers to the Acetylcholinesterase Enzyme AChE , which is the key enzyme in the hydrolysis of the neurotransmitter acetylcholine and is also the target of most of the clinically used drugs for the treatment of AD, but these drugs provide only symptomatic treatment and have the limitation of loss of therapeutic efficacy with time.
Several hybrid molecules incorporating the main sub-structures derived from diverse chemotypes like acridine, quinoline, carbamates, and other heterocyclic analogs have shown desired pharmacological activity with a good profile in a single molecule. This is followed by optimization of the activity through structural modifications guided by structure activity relationship studies, leading to the discovery of novel molecules 17b, 20, and 23 with desired AChE inhibition along with desirable activity against other above-mentioned targets for further pre-clinical studies .
The next review on xenobiotic metabolizing enzymes may find useful applications in related medical interventions or help in the development of more efficient drugs since xenobiotic metabolizing enzymes are important for the metabolism, elimination and detoxification of exogenous agents, and are found in most tissues and organs.
The next paper refers to antimicrobial activity of caffeic acid derivatives, selected based on computer-aided predictions. Twelve tested compounds have shown good antibacterial activity. Five out of twelve tested compounds appeared to be more active than the reference drugs ampicillin and streptomycin. Despite that all compounds exhibited good activity against all bacteria tested, the sensitivity of bacteria towards compounds in general was different.
The evaluation of antifungal activity revealed that all compounds were more active than ketoconazole, while seven compounds 2, 3, 4, 5, 7, 8 and 12 appeared to be more active than bifonazole. A simple but efficient route for the synthesis of novel 8—morpholinoaryl—2, 5-dihydro-3H-pyrazolo[4, 3-c]quinoline- 3-one derivatives is reported.
Molecular docking studies of synthesized compounds with human PDE5A protein shows that all the compounds exhibited good docking score in comparison with known inhibitors. In addition, all the synthesized molecules were evaluated against HCT cell lines for their antitumor activity. Compounds 5a, 5d, and 6e showed better cytotoxicity and can be studied as potential inhibitors of PDE5A . The first part of this issue mainly focuses on medicinal developments driven by functional peptides. This part is the continuation of drug discovery and design, but this time with emphasis on developments driven by functional molecules, especially drugs or their derivatives from natural products.
In the review regarding AD treatment, Wu et al. Although some natural products show promising preliminary results in AD treatment, they are still a long way from clinical transformation. A Chinese scientist Youyou Tu won the Nobel Prize in Physiology or Medicine because of the outstanding contribution to the discovery of antimalarial drug artemisinin that is extracted from an herbal prescription. Although artemisinin and its derivatives were primarily developed as antimalarial agents, later extensive studies have witnessed other pharmaceutical potentials beyond malaria.
Thus, the paper of Liu et al. Due to the therapeutic potential of histone deacetylases HDACs as one of promising drug targets in cancer, HDAC inhibitors have been intensively investigated over the last few decades. In the last review, Li et al. Finally, we would like to express our sincere gratitude to all authors, reviewers as well as the editorial staff of Current Topics in Medicinal Chemistry for their kind contributions and excellent support to this issue.
This editorial provides a brief overview of this thematic issue. The thematic issue is proposed to help medicinal chemists and biologists track the most recent insilico drug discovery research and high-throughput methods in molecular biochemistry. Traditional drug design strategy suffers from long periods of time and the high cost of drug development, which benefits from the recently developed computationbased drug discovery approaches.
These approaches include virtual drug screening, molecular dynamics, docking and epitope recognition. The collection of this thematic issue include six articles. The first one reviews the recent advances in in silico B-cell epitope prediction. The second one proposes a novel improved biogeography-based optimization and applies it to plant drug extraction. The third one focus on the proteinprotein interaction network analysis of virulence proteins of Aspergillus fumigatus.
The fourth one designs and synthesizes novel MAO inhibitors with antioxidant potential, and evaluates the former as novel multifunctional agents against monoamine oxidase A and B. The fifth article critically reviews the various in silico techniques, including 3D QSAR, COMFA, and molecular docking, for study of the natural product based xanthine oxidase inhibitors. The sixth reviews interactions between resveratrol and various ligands, and studies that focus on resveratrol using molecular docking strategies.
In the past few decades, the upsurge of various deadly diseases that mar our well being and progression is increasing the necessity to develop safe and effective theranostic methods. Further, these probes can provide biological information at the molecular level during disease process, which is consistent with the concept of precision medicine.
The first part of this present special issue mainly focuses on the recent developments and applications of peptide-based probes in medicinal chemistry, including peptide design based on machine learning, radionuclide-labeled peptides for cancer imaging and therapy, peptide-based nanoparticles, and drug delivery for cancer therapy. Although it represents only a small portion of current research, this issue strives to include several typical and significant topics contributed by extraordinary scholars in frontier research of this field.
We sincerely hope that these reviews foster interest and enthusiasm for functional peptides in theranostic applications. The papers included in this part can be summarized as follows: In the opening paper of this issue, Wu et al. Compared to traditional screening techniques, this accurate and effective technique will be of great benefit to the discovery of active peptides. Due to playing important roles in tumor initiation, progression and metastasis processes and over-expression in many solid tumor types, C-X-C chemokine receptor 4 CXCR4 has become a very important target for cancer imaging and therapy.
Although there were some minor flaws in preclinical studies, the promising data certainly promoted the translation of these probes to clinical application. Similarly, prostate-specific membrane antigen PSMA is considered a valuable target for both the diagnosis and therapy of prostate cancer. Diao et al.
For treatment of prostate cancer, Zhang et al. In their review, different types of therapeutic nanoparticles for prostate cancer, especially those based on targeting receptors such as PSMA or gastrin-releasing peptide GRP were described in detail to provide further understandings and recommendations on the design and development of targeted nanoparticles.
Our sincere thanks are due to the editorial staff for their great support during the whole process. Burgeoning rise in different disease cases such as cancer, viral diseases including Dengue, Chikungunya, Zika, Ebola, Japanese encephalitis, etc. Advances in scientific research have shown the impact in eradication and prevention of many diseases conditions such as polio. Interplay of experimental and theoretical approaches have come a long way in proving their effectiveness and worth in this regard.
Earlier computational approaches were almost ignored by a large section of the scientific community. Last few decades have witnessed a drastic change in the existing beliefs and today theoretical techniques are not only supporting and supplementing experimental results but also guiding studies by providing valuable cues.
Computational approaches pertaining to understanding complex biological system have come a long way during past few years rising from its infancy to blooming into a full-fledged science. Simple bioinformatics and chemo-informatics approaches are being frequently applied in the arena of system biology and are providing remarkable insights on unsolved and unanswered scientific questions so far. Battling diseases requires concerted efforts towards innovation and discovery.
Development of effective and commercially feasible therapeutic agents or drugs is a time consuming and labour—intensive process which thrives on an array of resources. It is assumed that application of Computer Aided Drug Design CADD for prospecting and profiling of new lead compounds in initial stages of drug discovery pipeline will offer many advantages both in terms of monetary gain and optimal use of available resources. Computational chemistry, a combinatorial subject has come a long way from its initial days of being considered as an auxiliary science to an indispensable part of most modern drug developmental programs.
As the trend shifted from one gene or protein approach towards the whole genome or proteome analysis in unveiling disease mechanism and progression, computational approaches slowly but steadily made their way in domain once owned exclusively by medicinal chemists or biologists.
The field has grown by leaps and bounds not only because of advances in computational technology, software development and processing speed but also because of mammoth scale and rapid pace of generation of experimentally derived data and myriad types of data available waiting to be analyzed and used. Computational approaches are touching all realms of life and have catapulted to a position where their crucial role in generating and validating hypotheses, disease identification, knowledge discovery, therapeutics and control by identification of novel drug targets, drug molecules and vaccines cannot be denied.
Some of the well known applications of computational approaches in drug designing include structure elucidation by molecular modeling, Quantitative Structure-Activity Relationships QSAR , docking and molecular simulation, toxicity prediction, machine learning and data mining approaches for data analysis and visualization. Considering the huge risks of reemergence and resurgence of infectious diseases and the problem of drug resistance along with the mounting costs of drug development programs and time gaps, it is only prudent to adopt and integrate computational techniques and programs in drug discovery pipelines to expedite the progress by turning the scale in our favor by cutting down costs of such ventures by shortening the drug discovery cycle and reducing efforts, manpower and time duration.
Computational approaches have now become an integral part in storage, management, comparative analysis and in obtaining in-depth knowledge of disease due to their versatility. Computer aided drug design, genomics and proteomics, metabolomics, interactomics play a crucial role in mining hidden molecular information, pattern recognition and finally interpretation of biological significance. Computational chemistry is being widely used at different stages of drug design and production like target identification, target validation, lead identification and lead optimization in the pharmaceutical industry and has emerged as powerful tools complementing traditional chemical screening methodology.
A synergistic relation between information technology and routine experimental approaches is required to handle and process voluminous and diverse datasets generated through genomics and high throughput screening methods and increasing the reliability of the outcomes. Incorporation of techniques based on artificial intelligence and use of large scale distributed computing for screening have provided a much needed impetus to drug discovery programs. Considering the array of disciplines and sub-disciplines involved with computational approaches and vast number of diseases we are dealing with, the topic requires series of issues to present the recent advancement and understanding on the subject.
Our aim as editors is to bring forth informative articles that highlight the ongoing research in the computational front with respect to various diseases. We received enormous response and witnessed enthusiasm from the researchers to contribute in this series of issues.
After successful completion of Part-I Volume 18, Number 13 , here we present the Part II Volume 18, Number 31 with some selected articles summarizing interesting application of the implementation of computational approaches. The article by Salam et al. Kaur and coworkers reviewed the structural insights required for the inhibition of HIV1 integrase . Novel computational analyses for screening Cryptococcus species have been thoroughly outlined by Manjunath and Skariyachan . Bashir and coworkers presented a general and overall perspective on the modern theoretical and computational aspects with respect to human diseases .
Kalra and coworkers highlighted the influence of physicochemical properties of functional groups such as ethers and esters at the 10th position of artemisinin derivatives in optimizing the anti-malarial activity . Tiwari and coworkers reported Acetate kinase AcK as a broad-spectrum novel target in Mycobacterium tuberculosis, Vibrio cholerae, and pathogenic Escherichia coli .
Our sincere thanks are due to Dr. Reitz, the Editor-in-Chief of Current Topics in Medicinal Chemistry for providing us this opportunity of bringing forth this special issue. It has been a great team effort. We would like to express our sincere thanks to Ms. We are thankful to the Editorial staff for their great support at every step of this issue. We are sincerely grateful to the authors for their contribution and patience during the review process. Contribution of the renowned reviewers deserves special mention; we acknowledge their support and efforts in scrutinizing manuscripts and providing valuable comments and suggestions for improving the quality of manuscripts.
We believe that this special issue will be interesting for the readers of the journal. Development of novel anti-cancer drugs is one of the most important theme in cancer research. Natural products and synthetic compounds have been searched extensively to cure different kinds of cancers and still search is on for finding novel compounds. Great effort has been done to find the target of anti-cancer drugs.
Further target specific compound is being developed to cure cancer. Correlation between structure and function is one of the important aspects for success of anti-cancer compounds. In recent years strategic drug development program against the cancer has been initiated including high throughput screening of compound using bioinformatics, various cell lines, patient-derived tumor xenografts and drug delivery system.
The purpose of this special thematic issue is to summarize the use of ongoing strategy for anti-cancer drug discovery and their valuable contribution for the expansion in the field of medicinal chemistry. Microbial Bioinformatics is a rapidly evolving field of study that not only encompasses health and food science areas, but also presents new opportunities for advancement and innovation in engineering, manufacturing, and industrial process improvements . As new sequencing methods become more cost effective and mobile, obtaining data for analysis is much less the obstacle than it once was .
The current resistance to widespread comprehensive data inclusion and diverse applied implementation of findings is the storage and computing power to analyze and organize raw data into usable and accessible formats. These hurdles will continue to be diminished with the improvement and application of new and more sophisticated algorithms as the artificial intelligence and cloud computing eases the current technological infrastructure burdens [5, 6]. The influx of omics data readily available for further analysis should be complemented by advancements in the structural modeling in order to ensure the structure-function relationships derived are sound.
The complementary effect of greater sequence and structural refinement inputs serve to aid predictive elements as well as engineering of biomolecules, small molecule products, and in silico systems with medicinal or industrial purposes. Primary sequences dictate later modifications and structure . To properly assess activity and function, the inclusive treatment of sequence, predicted modifications and corresponding structure, as well as the corresponding activities of such products in a systems perspective is imperative Computational systems biology.
Microbial systems have proven to be an invaluable simplistic model in systems biology, however when discussing medical microbiology in the context of antimicrobial design microbial system inputs are not easily directly transferable to human systems. This aspect may prove to be an advantage in development of antimicrobials that capitalize on these systematic differences in response to external perturbation A network property necessary for concentration robustness.
Longevity, spectrum of coverage, and reduced toxicity of an antimicrobial treatment prove to be the difference between a theoretically good drug candidate, a later phase failure, and a true blockbuster global health improvement dictating medication. Precision medicine and pharmacogenomics is becoming more mainstream, as are more diverse and comprehensive microbial diagnostics becoming more affordable and accessible.
The combination of systems analysis, structure-function relationships of small molecule drug candidates, and experimental findings from high-throughput screening and structural molecular dynamics validation methods provide improved stepping stones for drug discovery and development with expanded success limiting toxicity and maximizing the therapeutic effect [8, 9]. The complementation of experimental and computational sciences is ever apparent. As technological advancements in the areas of sequencing, data storage and acquisition, structural determinations, and systems biology arise, it is ever important that information is integrated and otherwise built upon for future studies to maximize available resources .
The academia to clinical availability factor of medicinally relevant small molecules will continue to improve, as will continually decreasing costs as more successful, promising leads are distinguished from less favorable leads earlier on and with greater ease in the drug discovery process [10, 11]. Distinguishing the winners from the losers earlier on in the drug discovery game will continue to contribute to less irrecoverable costs and less overall risk endured by drug manufactures in order to bring a new drug to market in an attempt to stay ahead of ever evolving microbial species presenting threats to human health globally, Drug Delivery: Principles and Applications.
Due to its receptor availability, it is so called as universal drug target for gram positive pathogens. In present review Chandra Bose Selvaraj et al. Now it is considered as a promising target for the development of new anti-infective drugs that aim to interfere with important Gram-positive virulence mechanisms, evasion of host defenses, and biofilm formation. Many inhibitors of sortase have been identified using high-throughput or in silico screening of compound libraries, and also have proved useful tools for probing the action model of the enzyme, several are also promising postulant for the development into potent inhibitors [15, 16].
These research advances have greatly contributed to our knowledge of sortase cell wall anchoring, providing a platform for therapeutic targeting and further study in industrial applications. Candidiasis is a most common fungal infection caused by yeasts that belong to the genus Candida. The antimicrobial activities of the isomers and enantiomers of pinene were evaluated against bacterial and fungal cells.
Macrotyloma uniflorum is an unexploited legume, which is rich in nutrients and promising therapeutic prospects. Manju Mohan et al. Future studies in this direction have to be performed to completely elucidate the characteristic features of Serine type protease inhibitor seed coat. An economical method to nullify the protease inhibitory activity which will increase the availability of a good protein source at a cheaper cost, thereby, making it a much needed protein source to meet the middle and lower class necessities .
The inhibitory effect of purified protease on trypsin activity was characterized by enzyme kinetic study. To better understand the mechanism of protein mobilization, undertaken the task of purifying and characterizing proteases, which occur transiently. The overall study revealed that MUPI is an insulin sensitizer, and can be considered as a potent bioactive compound for diabetes.
This innovative and challenging research will open up new avenues which constitute an effective anti-hyperglycemic protein which may find application in treatment of diabetes without evident toxic effects . STAT 3 is a latent cytoplasmic transcription factor which promote oncogenesis. STAT3 appears to be an important mediator of chemo resistance in osteosarcoma. Ravina et al. Initial approach is made via in silico method based on docking studies and pharmacophore profiling to identify best pre-established compound . Moreover a compound Sorafenib found to be best established drug with effective affinity towards the targeted protein.
Interestingly, on further virtual screening investigation the total energy of virtual screened compound Pubchem CID is better than the entire set of pre-established inhibitors with preferable affinity and inhibitory action. The study foresee Sorafenib and are structurally cognate. Howbeit Sorafenib is efficient inhibitor, but novel compound with great affinity towards STAT3 can be emerge as an important drug in treatment of disease the future ahead.
Although, this research will open up new horizons to deliberate further utilization in in vivo and in vitro analysis. This research will contribute in determining the most effective chemical prospective to fight against osteosarcoma. Kritika et al. Author rationalize the interaction of the CD20 with its pre-established inhibitors for CD and to render the new compound having high binding consonance against the target protein. By virtue of Insilco approaches which includes depiction of targeted protein structure and validation by Ramachandran Plot .
Further docking studies carried out in addition with pharmacophore and ADMET analysis for toxicity . Withal, conspicuous from the docking studies of pre-established and virtual screening  compound for CD resulted in among all compounds top side with PubChem Id found to have good affinity among all pre-established compound for desired protein receptor CD, whereas on compelling this study virtual screened compound with PubChem CID is inimitable for pharmacokinetics and it is preferable to pharmacological profile to prevent CLL cancer.
This innovative and challenging research will open up new avenues which constitute an effective protein CD which may find application in treatment of Chronic Lymphomatic Leukemia without evident toxic effects. Epigenetics is the heritable change in gene function that does not involve changes in the DNA sequence. To date, several types of epigenetic changes have been characterized, including methylation, hydroxymethylation, acetylation, phosphorylation, ubiquitination, neddylation and so on.
With the biological investigations of these modifiers, some of them are identified as promoters in the process of various diseases, such as cancer, cardiovascular disease and virus infection. Hence, targeting epigenetic modifiers has been considered as a promising strategy for disease treatment. To date, several epigenetic targeted drugs have entered clinic trials, or are currently being used in clinic, including a DNA methyltransferase inhibitor, bromo domain reader inhibitor, and histone acetylase or deacetylase inhibitor, histone methyltransferase or demethylase inhibitor, deubiquitinase inhibitor and neddylation inhibitor.
Most of these drugs are applied in leukemia, lymphoma therapy, or are combined with other drugs for the treatment of solid tumor. This issue provides the up-to-date summary on some epigenetic targets and the development for related inhibitors for cancer therapy. The first review by Prof. Zigang Li and co-authors comprehensively summarized the biological roles of epigenetic targets and related inhibitors developed for cancer therapy. The second review by Prof. Weisheng Feng et al. The third review by Dr.
Fanghui Lu et al. The fourth review by Prof. Hao Fang et al. The last review by Prof. Feng Liu et al. The important steps involved in the process of drug discovery are lead identification, lead optimizations, pre-clinical lead development, and clinical lead development. The contribution of computational design methods to lead identification and optimizations is no longer a matter of dispute. Exploitation of computational tools has not only reduced the cost but also the time in drug discovery. The last decade witnessed significant contributions of computational tools in many emerging areas of drug discovery viz.
This special issue aims to cover the full spectrum of computational approaches relevant for drug discovery. Let us now discuss the content of this issue. The first review article is focused on the identification of drug binding sites and includes a comparison of three common approaches namely sequence-based methods, structure-based methods and probe-based Molecular Dynamics MD methods to identifying drug binding sites. The subject of the following review article focusses on current status of application of ligand and structure-based approach targeting Anthrax virus.
The last manuscript is a research article related to ligand and structure-based investigation of structural requirements for silent information regulator 1 [SIRT1] activation. The important steps involved in the process of drug discovery are lead identification, lead optimization, pre-clinical lead development, and clinical lead development. The contribution of computational design methods to lead identification and optimization is no longer a matter of dispute.
Let us turn now to the content of this issue. The first review article talks about epidemics of viral diseases that adversely affects human population and the role of bioinformatic and immunoinformatic tools which can aid in vaccine design against these deadly diseases . The second article is a review related to the recent advances and limitations of current pharmacokinetic modeling approaches and reveal some possible solutions to improve the applicability of in silico Caco-2 permeability models for absorption property profiling .
The subject of the following review article deals with the molecular modeling approaches for the prediction of pharmacokinetic properties . Fourth review article offers us a vision on computational methods for binding mode and binding affinity prediction of peptide- MHC complexes . The last manuscript is a research article related to lipid lowering, anti-oxidant and anti-hyperglycemic activity of oxopropanylindole hydrazone derivatives . The series have published a total of four special issues up to date Part - V. In this sense, the issue presents a new collection of papers exploring the use of new methods of Medicinal Chemistry and Enabling Technologies in Drug Discovery.
The issue also discusses the new aspects emerging from the interaction of Medicinal Chemistry with Personalized Medicine towards the development of safer personalized drugs in the future. In this connection, the issue also discusses not only chemical and technical methods but also ethical and legal concerns.
As early success in perinatal medicine, nutrition, chronic diseases, cancer and trauma demonstrates, metabolomics is approaching feasibility in terms of guiding improvement in population level diagnosis and treatment. This review covers key advancements in clinical metabolomics and applies a high throughput metabolomics method as a proof of principle to identify novel metabolites associated with remote ischemic preconditioning .
Malik et al. Drugs obtained from natural sources play an important role in treatment of various pathological disorders and act as lead compound for the discovery of new synthetic drug substances. In this review various pharmacological effects produced by inhibition of xanthine oxidase and monoamine oxidase through natural and synthetic flavanoids as well as anthraquinones are discussed in detail. In this review, all the in-vitro and other computational approaches are critically discussed which provided the clue about structure activity requirements for further precise modifications on the basic scaffold .
Significant investment and remarkable researches surround the matter; however, not all those promising advances are reaching patients as quickly as they should. The absence of an adequate regulatory framework could be not helping. Some of them are the access to Personalized Medicine; the treatment of a large volume of sensitive information and the use of tools produced by "big data" systems in clinical care or in predictive models.
In addition, the legal protection of personal data related to health, the exercise of autonomy by patients, closely related to the regulation regarding clinical trials, are seriously involved. The purpose of this work is to review the regulations of the European Union, in this regard . Sharma et al. Induction of VEGF genes occur due to hypoxic condition induced by tumour growth after a critical size in cancerous cell. The aim of present study is to inhibit the VEGFR2 protein by the action of certain inhibitors and find the best one. A total of 23 potential inhibitors were searched and used to target the protein using the concept of molecular docking.
Ferreira et al. In this context, the objective of this study was to investigate the antifungal activity of isoeugenol, a phenylpropanoid, by in vitro and in silico assays against Penicillium citrinum strains. PASS online has shown that isoeugenol has the opportunity to present antiseptic, antifungal, antibacterial, antimycobacterial activities.
Molinspiration showed that the phytoconstituent has good potential for oral bioavailability. After analysis, it was verified that the isoeugenol have bactericidal effect against the strains of P. Infectious diseases, such as endocarditis, chronic skin infections, middle ear infections and sinusitis are responsible for over 15 million deaths a year . The high mortality rate is due to the widespread use of antibiotics in humans which cause increased resistance by bacterial strains. Moreover, bacteria in biofilms communicate by means of molecules, which activate genes responsible for the production of virulence factors quorum sensing mechanisms.
Current antibiotic therapy is generally effective against free-floating bacteria while it is often unproductive against pathogens forming biofilms because biofilm colonies can be up to times more resistant to conventional therapies . Increasing resistance to antibacterial agents has augmented the need for the development of new drugs and drug delivery approaches to treat infections [4, 5]. Investigations concerning the development of novel strategies to overcome antibiotic resistance represent a great challenge for both the academic world and industry since bacterial infections represent a significant issue that includes several areas such as public health or food contamination [6, 7].
This issue highlights the chemical and pharmacological features of novel compounds to treat antibacterial infections and recent therapeutic approaches to overcome antibiotic resistance. The papers included in this special issue confirmed the importance of both well-known natural products with low molecular weight and antimicrobial peptides in the management of chronic and nosocomial infections. However, natural antimicrobial peptides and polyphenolics derivatives could suffer from chemical instability, photosensibility, and enzymatic degradation, which hamper their clinical use.
Here, to overcome these limitations, medicinal chemistry approaches, such as chemical modifications, replacement of hydrolysis sensible groups or introduction of mimetics of natural amino acids, were analyzed and reported. Thus, this special issue collects latest advances in the field of antibacterial drug discovery and delivery such as the use of natural-based antibiofilm and antimicrobial peptides, naturally occurring prenyloxyphenylpropanoids, and polyphenolics as suitable clinical tools for the treatment of infections.
The guest editor wishes to thank all the researchers that contributed to this special issue and the anonymous reviewers that, with their helpful and constructive suggestions and comments, improved the quality of the final version of the papers. Infectious diseases cause remarkable human suffering, particularly in lowincome and middle-income countries.
Infectious diseases are responsible for the vast economic burden globally. Efforts are going on to develop effective and safe therapeutics, however the rapid appearance of drug resistance in human pathogens, weaken the clinical worth of several current drugs. Therefore, the discovery of new anti-infectious molecules is highly demanded. This special issue comprises the up-to-date information on drug development for infectious diseases.
The first contribution presents a review article focused on small molecules effective against liver and blood stage malarial infection was contributed by Dr. This mini-review article covers library of chemical compounds effective against blood stage and liver stage malarial infections i. The second contribution was received from Prof.
Samuel K. Kwofie and colleagues. This review focuses on the malarial aspartic proteases known as Plasmepsins Plms as novel drug targets and antimalarials targeting Plms. The group led, Prof. Alo Nag and co-workers from University of Delhi South Campus, India contributed the next review article about ionophores as potent anti-malarials. This review presents an overview on the state-of-the-art of the relevant literature on ionophores, and provides insight into the mechanism and prospects of different classes of ionophores as promising antimalarial.
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Next, two articles were contributed by Prof. The biological aspects of heme and its drug interactions with CYP have been reviewed. The last contribution is an research article that presents the designing of a novel indoline scaffold based antibacterial compound and pharmacological evaluation using chemoinformatics approaches.
We are grateful to all the authors and referees for their valuable support to this special issue. Research to discover new treatments for infectious disease has developed as a specialty during the past century. At global level, the burden of the infectious diseases is growing, particularly in low-income and middle-income countries, and susceptible populations. Infectious diseases trigger millions of deaths yearly. Widespread resistance of anti-infectious drugs remains a big threat, particularly when effective vaccines are not available for most of the infectious diseases.
Subsequently, inventions of new therapeutics effective against infectious diseases are highly required. This special issue of Current Topics in Medicinal Chemistry contains the latest updates on molecular mechanisms, drug targets, drug development for infectious diseases in the form of high-quality articles from the various parts of the world. Drugs often modulate unwanted targets that induce toxic effects on human cells. Unraveling the components of the biological network that induce the toxicity pathways is an integral component of drug toxicity studies at preclinical stage.
Cell-based dose—response assessments of toxicity rely on the detection of small cellular signals in response to perturbation of toxicity pathways. Zhang et al developed genetic circuitries, such as integral feedback, feedforward, and transcritical bifurcation, to obtain acceptable thresholds in response to changes in certain specific cellular states, such as levels of reactive oxygen species, oxygen molecules O 2 , DNA damage, protein folding, metal ions, or osmolarity.
Toxicity of drugs can also become an issue for engineered chassis organisms by limiting production titers. In order to reduce the toxicity effects, SB approaches have been proposed based on engineering export systems in the cell. Application of SB in DD is at its infancy. However, it already plays a major role in reorienting pharmaceutical research. The abundance of experimental chemical proteomics data has revealed the existence of multiple biological targets for a given drug.
This raises a systemic view of poly-pharmacology, which completely aligns with the cell-based phenotypic and holistic approaches of SB. The rational-based genetic design is to SB what rational-based drug design is to medicinal chemistry. The great success of SB in the field of bioproduction with the success story of artemisinin will likely influence the early stages of DD. Next future interests are likely in the rational design of new biochemicals through genetic shuffling of biosynthetic modules in order to be compliant with large-scale production within microorganisms.
Synthetic cells have not only become a biofactory for producing added value compounds or innovating new NP-like derivatives but also a wet laboratory in which, therapeutic target or cell signaling pathway can be tested. It also provides a rational approach to engineer cell-based assays to screen for compounds that will trigger the designed disease phenotype. Such cell-based phenotypic assay has the advantage to study the action of the drug on the entire therapeutic pathway. Disruption of interactions between such pathways including metabolism and cell signaling can be studied through such synthetic cell-based models.
The use of luminescent or fluorescent reporter genes is particularly useful to follow biomarkers of phenotypes with respect to physiological conditions. Designing synthetic QS is a powerful tool to study cell—cell communication within bacteria consortium and in order to overcome drug-resistance and persistence mechanisms.
Genetic circuits can reproduce artificial communication system and can be used to screen for compounds that disrupt QS or synergies between metabolism and drug resistance mechanisms. Indeed, sensitizing resistant or persistent bacteria using combination of antibiotics and metabolites is another promising approach to overcome drug resistance. The holy grail of SB in the field of DD is to create a universal cell in which NP biosynthesis could be selectively triggered by sensed disease phenotypes. Lead optimization could be made through selective pressure a precious optimization process offered by living systems induced by chosen substrates.
Modification of genome expression through environmental conditions eg, nutriment or small molecular inducers or light is another great property of living organisms, which can be modulated through SB and transformed into a therapeutic strategy to trigger molecular switches within pathological tissues. Moreno L, Pearson AD. How can attrition rates be reduced in cancer drug discovery? Expert Opin Drug Discov. Hu Y, Bajorath J.
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Annual Reports in Medicinal Chemistry, Volume 41
Biosci Biotechnol Biochem. Bench-top fermentative production of plant benzylisoquinoline alkaloids using a bacterial platform. Bioeng Bugs. When plants produce not enough or at all: metabolic engineering of flavonoids in microbial hosts. Front Plant Sci. Modular organization of genes required for complex polyketide biosynthesis.
FEBS Lett. Natural products version 2. Hertweck C. Decoding and reprogramming complex polyketide assembly lines: prospects for synthetic biology. Trends Biochem Sci. Drug discovery and natural products: end of an era or an endless frontier? Nucleic Acids Res. Seyedsayamdost MR. High-throughput platform for the discovery of elicitors of silent bacterial gene clusters. Synthetic biology of secondary metabolite biosynthesis in actinomycetes: engineering precursor supply as a way to optimize antibiotic production.
A roadmap for natural product discovery based on large-scale genomics and metabolomics. Next-generation sequencing approach for connecting secondary metabolites to biosynthetic gene clusters in fungi. Advances and current limitations in transcript-level control of gene expression. Refactoring the silent spectinabilin gene cluster using a plug and play scaffold. The re-emergence of natural products for drug discovery in the genomics era. Nat Rev Drug Discov.
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Assessing the combinatorial potential of the RiPP cyanobactin tru pathway. Diversity-oriented combinatorial biosynthesis of benzenediol lactone scaffolds by subunit shuffling of fungal polyketide synthases. Winter JM, Tang Y. Synthetic biological approaches to natural product biosynthesis. Functional optimization of gene clusters by combinatorial design and assembly.
Engineering plant metabolism into microbes: from systems biology to synthetic biology. Synthetic biology tools for bioprospecting of natural products in eukaryotes. Yeast synthetic biology platform generates novel chemical structures as scaffolds for drug discovery. Metabolic engineering of higher plants and algae for isoprenoid production. Adv Biochem Eng Biotechnol. Tholl D.
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Biosynthesis and biological functions of terpenoids in plants. A golden gate modular cloning toolbox for plants. Synthetic biology: biocircuits in synchrony. Klavins E. Lightening the load in synthetic biology. Ye H, Fussenegger M. Synthetic therapeutic gene circuits in mammalian cells. Synthetic biology in mammalian cells: next generation research tools and therapeutics. Nat Rev Mol Cell Biol. Lapique N, Benenson Y. Digital switching in a biosensor circuit via programmable timing of gene availability.
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Metabolism of agrochemicals and related environmental chemicals based on cytochrome Ps in mammals and plants. Pest Manag Sci. BMC Plant Biol. The challenges of cellular compartmentalization in plant metabolic engineering. Key applications of plant metabolic engineering. PLoS Biol. Combinatorial biosynthesis in plants: a p review on its potential and future exploitation.
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Expanding the fluorine chemistry of living systems using engineered polyketide synthase pathways. Natural product biosyntheses in Cyanobacteria : a treasure trove of unique enzymes. Beilstein J Org Chem. Exploring marine cyanobacteria for lead compounds of pharmaceutical importance. El Gamal AA. Biological importance of marine algae. Saudi Pharm J. Microbial chemical factories: recent advances in pathway engineering for synthesis of value added chemicals.
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