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AbstractMatrix Metalloproteinases-9 (MMP-9) is one of the important targets that play a vital role in various diseases such as cancer, Alzheimer’s, arthritis, etc. Traditionally, MMP-9 inhibitors have been unable to achieve selectivity to get around this target; thereby, novel mechanisms such as inhibition of activated MMP-9 zymogen (pro-MMP-9) have been discovered. The JNJ0966 was one of the few compounds that attained the requisite selectivity by inhibiting the activation of MMP-9 zymogen (pro-MMP-9). Since JNJ0966, no other small molecules have been identified. Herein, extensive in silicostudies were called upon to bolster the prospect of exploring potential candidates. The key objective of this research is to identify the potential hits from the ChEMBL database viamolecular docking and dynamics approach. Protein with PDB ID: 5UE4, having a unique inhibitor in an allosteric binding pocket of MMP-9, was chosen for the study. Structure-based virtual screening and MMGBSA binding affinity calculations were performed, and five potential hits were finalized. Detailed analysis of the best-scoring molecules was performed with ADMET analysis and molecular dynamics (MD) simulation. All five hits outperformed JNJ0966 in the docking assessment, ADMET analysis, and molecular dynamics simulation. Accordingly, our research findings imply that these hits can be investigated for in vitroand in vivostudies against proMMP9 and might be explored as potential anticancer drugs. The outcome of our research might contribute in expediting the exploration of drugs that inhibits proMMP-9.Communicated by Ramaswamy H. Sarma

AbstractFor coronaviruses, RNA-dependent RNA polymerase (RdRp) is an essential enzyme that catalyses the replication from RNA template and therefore remains an attractive therapeutic target for anti-COVID drug discovery. In the present study, we performed a comprehensive in silicoscreening for 16,776 potential molecules from recently established drug libraries based on two important pharmacophores (3-amino-4-phenylbutan-2-ol and piperazine). Based on initial assessment, 4042 molecules were obtained suitable as drug candidates, which were following Lipinski’s rule. Molecular docking implemented for the analysis of molecular interactions narrowed this number of compounds down to 19. Subsequent to screening filtering criteria and considering the critical parameters viz.docking score and MM-GBSA binding free energy, 1-(4-((2S,3S)-3-amino-2-hydroxy-4-phenylbutyl)piperazin-1-yl)-3-phenylurea (compound 1) was accomplished to score highest in comparison to the remaining 18 shortlisted drug candidates. Notably, compound 1displayed higher docking score (−8.069 kcal/mol) and MM-GBSA binding free energy (−49.56 kcal/mol) than the control drug, remdesivir triphosphate, the active form of remdesivir as well as adenosine triphosphate. Furthermore, a molecular dynamics simulation was carried out (100 ns), which substantiated the candidacy of compound 1as better inhibitor. Overall, our systematic in silicostudy predicts the potential of compound 1to exhibit a more favourable specific activity than remdesivir triphosphate. Hence, we suggest compound 1 as a novel potential drug candidate, which should be considered for further exploration and validation of its potential against SARS-CoV-2 in wet lab experimental studies.Communicated by Ramasawamy H. Sarma

AbstractPlasmepsin V (Plm V) is an essential aspartic protease required for survival of the malaria parasite, Plasmodium falciparum (Pf). Plm V is required for cleaving the PEXEL motifs of many Pfproteins and its inhibition leads to a knockout effect, indicating its suitability as potential drug target. To decipher new inhibitors of PfPlm V, molecular docking of four HIV-1 protease inhibitors active against PfPlmV was performed on Glide module of Schrödinger suite that supported saquinavir as a lead drug, and therefore, selected as a control. Saquinavir contains an important hydroxyethylamine (HEA) pharmacophore, which was utilized as backbone coupled with piperazine scaffold to build new library of compounds. Newly designed HEA compounds were screened virtually against Plm V. Molecular docking led to a few hits (1and 3) with higher docking score over the control drug. Notably, compound 1showed the highest docking score (–11.90 kcal/mol) and XP Gscore (–11.948 kcal/mol). The Prime MMGBSA binding free energy for compound 1(–60.88 kcal/mol) and 3(–50.96 kcal/mol) was higher than saquinavir (–37.51 kcal/mol). The binding free energy for the last frame of molecular dynamic simulation supported compound 1(–92.88 kcal/mol) as potent inhibitor of PfPlm V over saquinavir (–72.77 kcal/mol), and thus, deserves experimental validations in culture and subsequently in animal models.Communicated by Ramaswamy H. Sarma

AbstractThe ongoing pandemic due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused COVID-19 has emerged as a severe threat to the life of human kind. The identification and designing of appropriate and reliable drug molecule for the treatment of COVID-19 patients is the pressing need of the present time. Among different drug targets, the main protease of SARS-CoV-2 is being considered as most effective target. In addition to the drug repurposing, different compounds of natural as well as synthetic origins are being investigated for their efficacy against different drug targets of SARS-CoV-2 virus. In that context, the chromone based natural flavonols have also exhibited significant antiviral properties against different targets of SARS-CoV-2. The in silicostudies presented here discloses the efficacy of triarylchromones (TAC) as potential inhibitor against main protease of SARS-CoV-2. The molecular docking and ADMET study performed using 14 arylchromones which could easily be accessed through simple synthetic protocols, revealed best binding affinities in case of TAC-3 (–11.2 kcal/mol), TAC-4 (–10.5 kcal/mol), TAC-6 (–11.2 kcal/mol), TAC-7 (–10.0 kcal/mol). Additional validation studies including molecular dynamics simulation and binding energy calculation using MMGBSA for protein ligand complex for 100 ns revealed the best binding interaction of TAC-3, TAC-4, TAC-6, TAC-7 against main protease of SARS-CoV-2. Moreover, the in vitroand preclinical validation of identified compounds will help us to understand the molecular mechanisms of regulation of TACs against SARS-CoV-2.Communicated by Ramaswamy H. Sarma

AbstractThe SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) is responsible for the COVID-19 outbreak. The highly contagious COVID-19 disease has spread to 216 countries in less than six months. Though several vaccine candidates are being claimed, an effective vaccine is yet to come. A novel reverse epitomics approach, ‘overlapping-epitope-clusters-to-patches’ method is utilized to identify the antigenic regions from the SARS-CoV-2 proteome. These antigenic regions are named as ‘Ag-Patch or Ag-Patches’, for Antigenic Patch or Patches. The identification of Ag-Patches is based on the clusters of overlapping epitopes rising from SARS-CoV-2 proteins. Further, we have utilized the identified Ag-Patches to design Multi-Patch Vaccines (MPVs), proposing a novel method for the vaccine design. The designed MPVs were analyzed for immunologically crucial parameters, physiochemical properties and cDNA constructs. We identified 73 CTL (Cytotoxic T-Lymphocyte) and 49 HTL (Helper T-Lymphocyte) novel Ag-Patches from the proteome of SARS-CoV-2. The identified Ag-Patches utilized to design MPVs cover 768 overlapping epitopes targeting 55 different HLA alleles leading to 99.98% of world human population coverage. The MPVs and Toll-Like Receptor ectodomain complex shows stable complex formation tendency. Further, the cDNA analysis favors high expression of the MPVs constructs in a human cell line. We identified highly immunogenic novel Ag-Patches from the entire proteome of SARS CoV-2 by a novel reverse epitomics approach and utilized them to design MPVs. We conclude that the novel MPVs could be a highly potential novel approach to combat SARS-CoV-2, with greater effectiveness, high specificity and large human population coverage worldwide. Communicated by Ramaswamy H. Sarma

AbstractDrug re-purposing might be a fast and efficient way of drug development against the novel coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We applied a bioinformatics approach using molecular dynamics and docking to identify FDA-approved drugs that can be re-purposed to potentially inhibit the non-structural protein 9 (Nsp9) replicase and spike proteins in SARS-CoV-2. We performed virtual screening of FDA-approved compounds, including antiviral, anti-malarial, anti-parasitic, anti-fungal, anti-tuberculosis, and active phytochemicals against the Nsp9 replicase and spike proteins. Selected hit compounds were identified based on their highest binding energy and favorable absorption, distribution, metabolism and excretion (ADME) profile. Conivaptan, an arginine vasopressin antagonist drug exhibited the highest binding energy (-8.4 Kcal/mol) and maximum stability with the amino acid residues present at the active site of the Nsp9 replicase. Tegobuvir, a non-nucleoside inhibitor of the hepatitis C virus, also exhibited maximum stability along with the highest binding energy (-8.1 Kcal/mol) at the active site of the spike proteins. Molecular docking scores were further validated by molecular dynamics using Schrodinger, which supported the strong stability of ligands with the proteins at their active sites through water bridges, hydrophobic interactions, and H-bonding. Our findings suggest Conivaptan and Tegobuvir as potential therapeutic agents against SARS-CoV-2. Further in vitroand in vivovalidation and evaluation are warranted to establish how these drug compounds target the Nsp9 replicase and spike proteins.

To address the drug resistance, a series of novel boronic acid-containing diarylpyrimidine (DAPY) derivatives were designed viabioisosterism and scaffold-hopping strategies, and compound 10jyielded the most potent activity and turned out to be a single-digit nanomolar inhibitor towards the HIV-1 IIIB, L100I and K103N strains.

Hydroxyethylamine (HEA)-based novel compounds were synthesized and their activity against Plasmodium falciparum3D7 was assessed, identifying a few hits without any apparent toxicity. Hits 5cand 5dalso exhibited activity against resistant field strains, PfRKL-9 and PfC580Y. A single dose, 50 mg/Kg, of hits administered to the rodent parasite Plasmodium bergheiANKA exhibited up to 70% reduction in the parasite load. Compound 5dtested in combination with artesunate produced an additional antiparasitic effect with a prolonged survival period. Additionally, compound 5dshowed 50% inhibition against hepatic P. bergheiinfection at 1.56 ± 0.56 μM concentration. This compound also considerably delayed the progression of transmission stages, ookinete and oocyst. Furthermore, the toxicity of 5dassessed in mice supported the normal liver and kidney functions. Altogether, HEA analogues (5a–m), particularly 5d, are nontoxic multistage antiplasmodial agents with therapeutic and transmission-blocking efficacy, along with favorable preliminary pharmacokinetic properties.

NendoU (NSP15) is an Mn(2+)-dependent, uridylate-specific enzyme, which leaves 2′-3′-cyclic phosphates 5′ to the cleaved bond. Our in-house library was subjected to high throughput virtual screening (HTVS) to identify compounds with potential to inhibit NendoU enzyme, high-rank compounds (those that bound to multiple target structures) were further subjected to 100 nanoseconds MD simulations. Among these, one was found to be bound highly stable within the active site of the NendoU protein structure. Here, we are reporting a derivative of piperazine based ‘(2S,3S)-3-amino-1-(4-(4-(tert-butyl)benzyl)piperazin-1-yl)-4-phenylbutan-2-ol’ (IV) from our in-house libraries having potential efficacy against SARS-CoV-2 in in vitro assays. This compound demonstrated inhibition of viral replication at the same level as Ivermectin, a known SARS-CoV-2 inhibitor, which is not used due to its toxicity at a higher than the currently approved dosage. Compound IVwas not toxic to the cell lines up to a 50 μM concentration and exhibited IC50sof 4.97 μM and 8.46 μM in viral entry and spread assay, respectively. Therefore, this novel class of NendoU inhibitor could provide new insights for the development of treatment options for COVID-19.

Malaria remains one of the world's most life-threatening diseases and, thus, it is a major public health concern all around the world. The disease can become devastating if not treated with proper medication in a timely manner. Currently, the number of viable treatment therapies is in continuous decline due to compromised effectiveness, probably owing to the complex life cycle of Plasmodium falciparum.The factors responsible for the unclear status of malaria eradication programmes include ever-developing parasite resistance to the most effective treatments used on the frontline (i.e., artemisinin derivatives) and the paucity of new effective therapeutics. Due to these circumstances, the development of novel effective drug candidates with unique modes of action is essential for overcoming the listed obstacles. As such, the discovery of novel chemical compounds based on validated pharmacophores remains an unmet need in the field of medicinal chemistry. In this area, functionalized phthalimide (Pht) analogs have been explored as potential candidates against various diseases, including malaria. Pht presents a promising bioactive scaffold that can be easily functionalized and thus utilized as a starting point for the development of new antimalarial candidates suitable for preclinical and clinical studies. In this short review, we highlight a wide range of Pht analogs that have been investigated for their activity against various strains of Plasmodium falciparum.

The novel coronavirus, SARS-CoV-2, has caused a recent pandemic called COVID-19 and a severe health threat around the world. In the current situation, the virus is rapidly spreading worldwide, and the discovery of a vaccine and potential therapeutics are critically essential. The crystal structure for the main protease (Mpro) of SARS-CoV-2, 3-chymotrypsin-like cysteine protease (3CLpro), was recently made available and is considerably similar to the previously reported SARS-CoV. Due to its essentiality in viral replication, it represents a potential drug target. Herein, a computer-aided drug design (CADD) approach was implemented for the initial screening of 13 approved antiviral drugs. Molecular docking of 13 antivirals against the 3-chymotrypsin-like cysteine protease (3CLpro) enzyme was accomplished, and indinavir was described as a lead drug with a docking score of −8.824 and a XP Gscore of −9.466 kcal/mol. Indinavir possesses an important pharmacophore, hydroxyethylamine (HEA), and thus, a new library of HEA compounds (>2500) was subjected to virtual screening that led to 25 hits with a docking score more than indinavir. Exclusively, compound 16with a docking score of −8.955 adhered to drug-like parameters, and the structure–activity relationship (SAR) analysis was demonstrated to highlight the importance of chemical scaffolds therein. Molecular dynamics (MD) simulation analysis performed at 100 ns supported the stability of 16within the binding pocket. Largely, our results supported that this novel compound 16binds with domains I and II, and the domain II–III linker of the 3CLproprotein, suggesting its suitability as a strong candidate for therapeutic discovery against COVID-19.

ABSTRACTIntroductionThe unique physicochemical properties and chemical diversity of organofluorine compounds have remarkably contributed for their wide utility in the area of pharmaceuticals, materials and agrochemicals. The noteworthy characteristics of fluorine include high electron affinity, lipophilicity and bioavailability, extending the half-life of the drugs. The incorporation of fluorine substituents, particularly trifluoromethyl groups, into organic molecules has led to their high potency against various diseases, including malaria. Hence, organofluorinated molecules offer valuable avenues for the design of new drug candidates against malaria.Areas coveredIn this review, the authors discuss the importance of fluorine substituents present in the chemical compounds, and their potential applications for antimalarial drug discovery.Expert opinionFluorinated molecules represent a reliable strategy to develop new antimalarial drugs. Fluorine or fluorinated groups have been identified as a promising precursor, and their presence in approximately twenty-five percent of approved drugs is notable. Selective fluorination of chemical entities has the potential to be applied not only to improve the activity profile against the malaria parasite, but could be extrapolated for favorable pharmacological applications. Hazardous reagents such as HF, F2and SF4used for fluorination, are not considered as safe, and therefore, this process remains challenging, particularly for the pharmaceutical industry.

The global prevalence of leishmaniasis has increased with skyrocketed mortality in the past decade. The causative agent of leishmaniasis is Leishmania species, which infects populations in almost all the continents. Prevailing treatment regimens are consistently inefficient with reported side effects, toxicity and drug resistance. This review complements existing ones by discussing the current state of treatment options, therapeutic bottlenecks including chemoresistance and toxicity, as well as drug targets. It further highlights innovative applications of nanotherapeutics-based formulations, inhibitory potential of leishmanicides, anti-microbial peptides and organometallic compounds on leishmanial species. Moreover, it provides essential insights into recent machine learning-based models that have been used to predict novel leishmanicides and also discusses other new models that could be adopted to develop fast, efficient, robust and novel algorithms to aid in unraveling the next generation of anti-leishmanial drugs. A plethora of enriched functional genomic, proteomic, structural biology, high throughput bioassay and drug-related datasets are currently warehoused in both general and leishmania-specific databases. The warehoused datasets are essential inputs for training and testing algorithms to augment the prediction of biotherapeutic entities. In addition, we demonstrate how pharmacoinformatics techniques including ligand-, structure- and pharmacophore-based virtual screening approaches have been utilized to screen ligand libraries against both modeled and experimentally solved 3D structures of essential drug targets. In the era of data-driven decision-making, we believe that highlighting intricately linked topical issues relevant to leishmanial drug discovery offers a one-stop-shop opportunity to decipher critical literature with the potential to unlock implicit breakthroughs.

Malaria is a major global health concern with the majority of cases reported in regions of South-East Asia, Eastern Mediterranean, Western Pacific, the Americas, and Sub-Saharan Africa. The World Health Organization (WHO) estimated 216 million worldwide reported cases of malaria in 2016. It is an infection of the red blood cells by parasites of the genus Plasmodium with most severe and common forms caused by Plasmodium falciparum (P. falciparum or Pf) and Plasmodium vivax (P. vivax or Pv). Emerging parasite resistance to available antimalarial drugs poses great challenges to treatment. Currently, the first line of defense includes artemisinin combination therapies (ACTs), increasingly becoming less effective and challenging to combat new occurrences of drug-resistant parasites. This necessitates the urgent need for novel antimalarials that target new molecular pathways with a different mechanism of action from the traditional antimalarials. Several new inhibitors and potential drug targets of the parasites have been reported over the years. This review focuses on the malarial aspartic proteases known as plasmepsins (Plms) as novel drug targets and antimalarials targeting Plms. It further discusses inhibitors of hemoglobin-degrading plasmepsins Plm I, Plm II, Plm IV and Histo-aspartic proteases (HAP), as well as HIV protease inhibitors of plasmepsins.

Malaria is a lethal disease causing devastating global impact by killing more than 8,00,000 individuals yearly. A noticeable decline in malaria related deaths can be attributed to the most reliable treatment, ACTs against P. falciparum. However, the cumulative resistance of the malaria parasite against ACTs is a global threat to control the disease and, therefore the new effective therapeutics are urgently needed, including new treatment approaches. Majority of the antimalarial drugs target BS malarial infection. Currently, scientists are eager to explore the drugs with potency against not only BS but other life stages such as sexual and asexual stages of the malaria parasite. Liver Stage is considered as one of the important drug targets as it always leads to BS and the infection can be cured at this stage before it enters into the Blood Stage. However, a limited number of compounds are reported effective against LS malaria infection probably due to scarcity of in vitro LS culture methods and clinical possibilities. This mini review covers a range of chemical compounds showing efficacy against BS and LS of the malaria parasite’s life cycle collectively (i.e. dual stage activity). These scaffolds targeting dual stages are essential for the eradication of malaria and to evade resistance.

Background: Despite the substantial progress over the time, malaria remains a major public health concern and causing hundreds of thousands of deaths. Resistance to the available antimalarial therapy increases threat to the global public health. Objective: Overview of currently available antimalarials. Method: Literary survey. Results: The summarized data about different types of antimalarial therapies and their efficiency and modes of action. Conclusion: Despite the seemingly large number of the drugs currently available for malaria treatment, this arsenal is limited due to the narrow variation of their mechanism of action.

In the current landscape of antiretroviral options, there remains an urgent need for novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) with improved resistance profiles and safety properties. Herein, a series of novel tetrahydropyrido[4,3-d]pyrimidine derivatives were discovered utilizing the “escape from flatland” strategy. The most potent inhibitor 10cwas endowed with broad-spectrum antiviral activity and improved resistance profiles against NNRTI-resistant variants compared to efavirenz and etravirine. Molecular simulations were investigated to furnish insights into the biological results. Drug-likeness assessment showed that 10cexhibited desirable physicochemical properties and in vitro metabolic stability. Notably, lower cytochrome P450 inhibition and human ether-à-go-go-related gene blockade liability were observed for 10cthan those for etravirine and rilpivirine. Besides, 10cwas characterized by excellent in vivo safety properties without acute/subacute toxicity and organ pathological damage. Overall, our multiparameter optimization campaign led to the identification of 10cwith excellent antiviral activities and favorable drug-like profiles that could serve as an ideal drug candidate for further development.

Among the diversity of natural and synthetic compounds being studied and applied for human welfare, peptides able to develop nanostructures are currently under special attention of scientists. In this review, we focus on such properties of peptides and various kinds of intramolecular interactions allowing their ability to form different shapes of nanoassemblies. We have also discussed the applications of self-assembled peptides in various biomedical fields where they can be employed as cargo to target delivery of drugs, genes, in tissue engineering, regenerative medicines, and biosensors.

Hydrogels have emerged as an unique and potential transporters for the target drug delivery systems in cancer therapy. Cancer is a terrible disease extracting toll on human health across the world probably due to several drawbacks of the conventional cancer treatments. However, hydrogels facilitate the modern and improved prospects for the treatment of cancer with minimum cytotoxic effects to the healthier cells or tissues. Besides, the easy tailoring associated with the structural features and high biocompatibility of hydrogels have attracted enough attention and offer them as a strong tool for the development of nanomedicine. This review is devoted to update the current studies related to hydrogels and their applications as vectors for cancer chemotherapy.

The novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) has led to a global crisis by infecting millions of people across the globe eventually causing multiple deaths. The prominent player of the virus has been known as the spike protein which enters the host system and leads to the infection. The S2 subunit is the most essential in this process of infection as it helps the SARS-CoV-2 to infect the host by binding to the human angiotensin converting enzyme 2 (hACE2), with the help of the receptor binding domain found at the S2 subunit of the virus. Studies also hypothesize that the S glycoproteins present in the virus interacts with different hosts in different ways which might be due to the mutations taking place in the genome of the virus over time. This work aims to decipher the similarities and differences in the sequences of spike proteins from samples of SARS-CoV-2 acquired from different infected individuals in different countries with the help of in silico methods such as multiple sequence alignment and phylogenetic analysis. It also aims to understand the differential infection rates among the infected countries by studying the amino acid composition and interactions of the virus with the host.

Head and neck squamous cell carcinoma (HNSCC) is the six most common cancer globally and most common cancer in men in India. The metabolic regulation is highly altered and is considered as a hall mark of HNSCC. TP53-induced glycolysis and apoptosis regulator (TIGAR) plays very important role in the development and progression of HNSCC. The aim of our study is to identify a novel FDA approved anticancer inhibitor against mutated TP53-induced glycolysis and apoptosis regulator (TIGAR) through drug repurposing approach. A library of 105 FDA approved anticancer compounds were screened using molecular docking approach against TIGAR (PDB: 3DCY) both Wild-Type (WT) and mutated (Mut). Specific mutations in TIGAR were identified using cBioPortal, a cancer genomics database and mutated structure was modelled using SWISS-MODEL. Out of 510 sequenced cases/patients samples, 17(3%) patients showed alteration in TIGAR [TIGARWTand TIGARMut (R88W)]. The virtual drug screening showed 45 drugs out of 105 high binding affinity with TIGAR, Trabectedin showed highest binding affinity with both TIGARWT(− 13.3 kcal/mol) as well as TIGARMut (R88W)(− 13.8 kcal/mol). The molecular docking studies were validated using molecular dynamics simulation (MD Simulation) of protein–ligand complex of TIGAR and Trabectedin for 100 ns. The MD Simulation of Trabectedin complex showed more stable with TIGARMut (R88W)compared to TIGARWT. Moreover, the string analysis revealed that metabolic-related genes, HK2, PFKFB1, PFKM, PFKP, PFKL, FBP1 are closely associated with TIGAR in HNSCC. Our findings suggest that Trabectedin can be proposed as an inhibitor for [TIGARMut (R88W)] which can be used to target metabolic signalings in HNSCC. However, further investigation and in vitro and in vivo validation our findings required to understand the molecular mechanisms of regulation of Trabectedin in HNSCC.