Letters in Drug Design & Discovery - Volume 17, Issue 12, 2020

Background: In the 1960s, the human coronavirus was designated, which is responsible for the upper respiratory tract disease in children. Back in 2003, mainly 5 new coronaviruses were recognized. This study directly pursues to govern knowledge, attitude and practice of viral and droplet infection isolation safeguard among the researchers during the outbreak of the COVID-19. Introduction: Coronavirus is a proteinaceous and infectious pathogen. It is an etiological agent of severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS). Coronavirus, appeared in China from the seafood and poultry market last year, which has spread in various countries, and has caused several deaths. Methods: The literature data has been taken from different search platforms like PubMed, Science Direct, Embase, Web of Science, who.int portal and complied. Results: Corona virology study will be more advanced and outstanding in recent years. COVID-19 epidemic is a threatening reminder not solely for one country but all over the universe. Conclusion: In this review article, we encapsulated the pathogenesis, geographical spread of coronavirus worldwide, also discussed the perspective of diagnosis, effective treatment, and primary recommendations by the World Health Organization, and guidelines of the government to slow down the impact of the virus are also optimistic, efficacious and obliging for the public health. However, it will take a prolonged time in the future to overcome this epidemic.

Background: Oxidative stress is a defense mechanism against malarial intracellular parasite infection. On the other hand, the Human glutathione reductase enzyme reduces oxidative stress in the cells, making the inhibitors of this enzyme a promising candidate for malaria treatment. Objective: Rational drug design was used in this work to plan new human glutathione reductase inhibitors. Methods: Virtual screening was performed using the ZINC database and molecular docking was used to detect appropriate human glutathione reductase inhibitors. Based on the docking scores obtained, the top three highest-ranked ligands were selected for the molecular dynamics simulation study. The MD simulation was performed for each complex in a length of 100 ns. Results: RMSD, RMSF and hydrogen bond analyzes were performed on the derived trajectories. Molecular mechanics generalized born surface area (MM-GBSA) and pairwise per-residue free energy decomposition analyzes were performed for the determination of binding free energy and the determination of dominant residues involved in the binding process, respectively. The binding free energy analysis showed that the molecule of 3-((7-(furan-2-ylmethyl)-5,6-diphenyl-7H-pyrrolo[2,3- d] pyrimidin-4-yl) amino) propan-1-ol is the most potent inhibitor among the molecules considered against human glutathione reductase enzyme. Conclusion: This molecule can be considered a novel candidate for antimalarial treatments.

Background: Type-2-diabetes mellitus is associated with many side effects affecting vital body organs, especially heart. Thiazolidinediones are potent antidiabetics. Studies have proven that amino-acids and peptides promote glucose transport, have antioxidant properties, and fewer side effects, thus we designed hybrids by combining amino-acid esters and peptide esters with 2, 4 thiazolidinedione acetic acid moiety which can act as antidiabetic agent with cardioprotection properties. Methodology: In vitro ADME, toxicity, and docking studies were performed using Qikprop3.1.OSIRIS, PROTOX (Prediction of Rodent Oral Toxicity), and FlexX 2.1.3, respectively. Results: All the designed molecules belong to three sub-series, i.e. 2, 4-dioxothiazolidine-5-acetic acid single amino acid hybrid methyl esters, 2, 4-dioxothiazolidine-5-acetic acid dipeptide hybrid methyl esters and 2, 4-dioxothiazolidine-5-acetic acid tripeptide hybrid methyl esters. All molecules were non-toxic. SSMA2, SSMA14, SSMA49, and SSDM50 showed good docking scores in 2PRG and 2UV4, respectively. Conclusion: The selected in silico studies helped to design hybrids with less toxicity, target specificity with dual activity as potential anti-diabetic and cardioprotective agents.

Background: Designing and development of molecules for cancer treatment useful and with no side effects are a big challenge for the researchers in the field of drug discovery. The use of phytochemicals for chemoprevention is gaining more advantages, and intake of flavonoids has proved to reduce the occurrence of various cancers. Objectives: The present study was focused on selecting eight flavonoids and study them by in silico methods to analyse the interactions, affinity and pharmacophoric features that participate in the interactions between the flavonoid and the active sites of different cancer targets. Methods: The cancer targets were downloaded from the protein data bank, and flavonoids from PubChem and were docked by Glide XP molecular docking method to find the molecular interactions. The binding energy was calculated by Prime MM-GBSA application and ADMET analysis by Qikprop of Schrodinger. The anticancer potential of flavonoids screening was based on an online tool, Pass predictor. Phase module was used to find the common pharmacophore features that participate in essential interactions between the flavonoid and the active site. Results: In this study, myricetin has proved to be the best flavonoid for the treatment of breast and lung cancer with docking score of -11.50 kcal/mol and -10.56 kcal/mol respectively, whereas, quercetin has proved to be the best for prostate and colorectal cancer with docking score of -14.18 kcal/mol and -12.94 kcal/mol, respectively. The responsible forces for the interaction of these flavonoids are hydrogen bond, hydrophobic interactions, polar and pi-pi stackings. The PASS tool predicted the anticancer potential for the flavonoids, in particular, myricetin had responded highly active for most cancer cells. The hypothesis AADRR_1 has the highest survival score, which indicates the best alignment of the active ligands and represents the best pharmacophore model for anticancer activity. Conclusion: This work has screened eight flavonoids against various cancer targets and shown the binding interactions between them, stating that myricetin is the suitable lead candidate for breast and lung cancer; whereas, quercetin is the best lead for prostate and colorectal cancer. And these data are about the results obtained from PASS predictor. Moreover, the pharmacophore model has generated for the flavonoids, which correlate activities with the spatial arrangement of various chemical features. Therefore, this investigation strongly suggests that these flavonoids can be used as leads as anticancer agents.

Background: Cancer is the name given to various diseases that are mainly uncontrolled, related to cell growth and can affect various organs. Among them, lung cancer is the one, which, in its earliest stages, is difficult to diagnose, and it is asymptomatic until the disease progresses. Triazole ring is an important heterocyclic ring known with various pharmacological activities. Objective: It is aimed to synthesize and characterize novel 1,2,4-triazole derivatives and screen them for in vitro antiproliferative activity and binding analysis through docking studies. Method: In this study, we have synthesized new 2-[[5-[(4-aminophenoxy)methyl]-4-phenyl-4H- 1,2,4-triazol-3-yl]thio]-N-(substituted aryl)acetamide (5a-h) derivatives and investigated their anticancer activities against human lung cancer (A549) and mouse embryo fibroblast cell lines (NIH/3T3) by MTT, flow cytometric, caspase-3 and matrix metalloproteinase-9 (MMP-9) inhibition assays. Results: Compounds 5f, 5g and 5h showed the highest cytotoxicity and caused significant apoptosis. These compounds inhibited MMP-9, slightly whereas they did not effect caspase-3. Conclusion: 5f namely, N-(5-acetyl-4-methylthiazol-2-yl)-2-((5-((4-aminophenoxy)methyl)-4- phenyl-4H-1,2,4-triazol-3-yl)thio)acetamide exhibited as the most active compound with selective cytotoxicity and the highest MMP-9 inhibition. Besides, molecular modelling assessment was signified that antiproliferative activity of the compounds 5f, 5g and 5h was through a slight MMP-9 inhibition pathway.

Background: The intentional dissemination of the “anthrax letter” led the researchers to increase their efforts towards the development of medical countermeasures against anthrax bioterrorism. A virulent strain of Bacillus anthracis secretes deadly three protein exotoxin (protective antigen, lethal factor and edema factor) that is the causative agent of anthrax and considered as serious biological weapons. Objective: Due to limited existing therapeutics options, there is still an insecure situation to combat anthrax. This prompted us to design a multifunctional inhibitor instead of a traditional one that competes simultaneously with the Protective Antigen (PA), Lethal Factor (LF) and Edema Factor (EF) for their binding sites. Methods: We integrated a pharmacophore modeling approach with the virtual screening and molecular docking analysis in the context of unique structural characteristics of deadly anthrax toxins. Results: Initially, we screened 56,000 natural compounds against designed pharmacophore consensus that returned 351 hits. Out of these initial screening hits, only 100 compounds passed out through Lipinski filter that comprised of 12 chemically relevant clusters. By exclusion of duplicate and based on their fit score in each cluster, 15 unique compounds were selected for detailed study. Putative multifunctional compounds subjected to deep structural analysis in the milieu of anthrax toxins binding pockets to gauge critical structural crunch. Conclusion: Our integrative approach provides a novel therapeutic window to develop a small molecular inhibitor that simultaneously targets three components of anthrax deadly toxin at the molecular level to elicit the desired biological process.

Background: Currently, infectious diseases caused by pathogenic and resistant bacteria are more challenging for anti-bacterial drug discovery. The discovery of new anti-bacterial agents developed in many mechanisms includes disruption of the bacterial cell wall formations. The MurA is a key enzyme contributing to the first step of bacterial peptidoglycan biosynthesis and is, therefore, proposed as an effective bactericidal target. Objective: The purpose of this research is to identify anti-bacterial compounds from U. gambir Roxb and to predict the potential inhibitory activities against murA enzyme by in silico study. Materials and Methods: Investigation and discovery of new inhibitors of MurA enzyme were conducted on the medicinal plant of Gambir (Uncaria gambir Roxb) and those that reportedly contained anti-bacterial agents. The anti-bacterial compounds were isolated by combinations of chromatography methods guided by anti-bacterial activity against bacteria of E. faecalis, S. mutans, and S. sanguinis. The structures of active compounds were characterized by spectroscopic methods, and the anti-bacterial activity was evaluated by the microdilution method (in vitro) combined with molecular docking of the MurA enzyme (in silico). Results: The anti-bacterial flavonoids of catechin were isolated from U. gambir Roxb with MIC values of 6250 and 12500 ppm, respectively, against S. sanguinis and E. faecalis. The in silico study showed that catechin has a binding affinity of -8.5 Kcal/mol to MurA which is higher than fosfomycin as a positive control. Conclusions: The catechin is predicted to have potential as a new natural inhibitor of the MurA enzyme to inhibit bacterial cell wall biosynthesis.

Background: Pyrimidine ring is one of the most important heterocyclic scaffolds due to its biological benefits as antimicrobial agents via acting as competitive suppressors of dihydropteroate synthase (DHPS) enzyme, inhibiting dihydrofolate reductase or glucosamine N-phosphate synthase. Objective: The objective of this work is preparing twenty four derivatives of pyrimidine heterocycle 1a-f, 2a-f, 3a-f and 4a-f via a facile one step reaction with antimicrobial potential. Methods: Novel twenty four derivatives of pyrimidine heterocycle 1a-f, 2a-f, 3a-f and 4a-f were prepared via a facile one step reaction by treating substituted aldehydes, urea and / or thiourea and active methylene derivatives (diethyl malonate and / or ethyl cyanoacetate) using 1,4- diazabicyclo[2.2.2]octane (DABCO) as a basic catalyst. The chemical structures of all these novel targets were proved by 1HNMR, 13CNMR, MS and elemental analyses. All the twenty four new targets 1a-f, 2a-f, 3a-f and 4a-f were assessed for their antimicrobial activity towards bacteria as Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli and against fungi represented by Aspergillus flavus and Candida albicans. Results: Most of the compounds exhibited very good antimicrobial activity, especially; compound (1c) exhibited the most activity against three types of bacteria Escherichia coli, Bacillus subtilis, Staphylococcus aureus. Moreover, this derivative 1c displayed similar antifungal activity towards Candida albicans as that exhibited by amphotericin B. Conclusion: All the screened compounds 1a-f, 2a-f, 3a-f and 4a-f showed antibacterial activity with inhibition zone diameter range 6-21 mm/mg, while, regarding the antifungal activity, all the novel derivatives except 2b, 2d, 3a, 3c, 3e did not have any effect towards Aspergillus flavus and 3d did not reveal any inhibitory activity towards both fungal species.

Background: Cancer is a leading cause of deaths worldwide, accounting for 9.6 million deaths in 2018. According to the WHO, the most common causes of cancer deaths are lung, colorectal, stomach liver and breast cancer. Introduction: PARP-1 has a crucial role in cell proliferation, survival and death due to its role in the regulation of multiple biological processes. Quinazolinone and its derivatives represent a large class of biologically active compounds that exhibit a broad spectrum of biological activities such as anti-HIV, anticancer, antifungal, antibacterial, anticonvulsant, anti-inflammatory, antidepressant, antimalarial, antioxidant and antileishmanial activities. Methods: In this study, we have synthesized quinazolinone derivatives by reaction of 2- aminobenzamide and substituted benzaldehydes. The synthesized compounds were also screened in silico for their PARP-1 binding affinities by molecular docking studies using Schrodinger 2016 software. In silico ADME studies were also performed for the synthesized compounds by using QikProp tool of Schrodinger software. Results: Results of in silico studies indicated that quinazolinone derivatives exhibited a good affinity towards the active site of PARP-1. Out of all synthesized compounds, SVA-11 exhibited a maximum dock score (-10.421). Results of ADME studies indicated the suitability of synthesized compounds as drug candidates. Conclusion: The synthesized compounds showed better docking scores than reference drug valiparib. Furthermore, they exhibited favorable ADME profile. Therefore, they may serve as lead compounds in the discovery of PARP-1 inhibitors.

Background: NSAIDs are used as first-line drugs for the treatment of various inflammatory disorders. Chronic use of NSAIDs is known to be associated with gastrointestinal and renal toxicity. Local generation of reactive oxygen species finally resulting in cellular apoptosis is one of the accepted mechanisms for NSAID-induced toxicity. Objective: The objective of the present study was to design and synthesize a series of 2-methane sulfonamido substituted arylthiazole derivatives by including structural features of combined antiulcer and anti-inflammatory activity utilizing as the structural core, thiazole nucleus with potential for antioxidant effect. Methods: Compounds were designed based on three dimensional and field similarity studies. The synthesized compounds were evaluated for their anti-inflammatory activity in carrageenan-induced rat paw edema model. Rofecoxib and indomethacin were taken as standard drugs for comparison. The in vitro antioxidant activity was assessed in potassium ferricyanide reducing power (PFRAP) assay employing ascorbic acid as the standard drug. Results: The compounds 6 and 7 showed good anti-inflammatory activity comparable to the standard group and were also non ulcerogenic at the test doses. Compounds 1-7 displayed varying degrees of reducing power in the PFRAP) assay and the methanesulphonamido derivatives 4-7 showed the highest antioxidant activity (EC50 values 3.7-5.1 μmol/ml vs ascorbic acid 7.4 μmol/ml). Theoretical ADME profiling of the compounds based on selected physicochemical properties showed excellent compliance with Lipinski’s rule. Conclusion: A series of compounds have been designed and synthesized having dual antioxidant and anti-inflammatory activity with activities comparable to standard drugs.

Background: The use of antibiotics has compromised due to the appearance of multidrug- resistant strains and decreased susceptibility of strains to antibiotics. Antibiotic resistance has become a worldwide threat as well as Helicobacter pylori induced gastric cancer is a major problem nowadays. Therefore, it is the need of time to synthesize potent anti-urease motifs. Introduction: Schiff bases represent a large class of biologically active compounds that exhibited a broad spectrum of biological activities. Amikacin is an important drug used against multidrugresistant species of microbes. Therefore, imine derivatives of amikacin may help to reduce the resistance of microbes and to treat the Helicobacter pylori induced stomach problems by inhibiting the Helicobacter Pylori Urease enzyme. Methods: Schiff bases of amikacin were synthesized and screened for in-vitro antibacterial assay performed by well diffusion method against Bacillus megaterium (Bm), Bacillus subtilis (Bs), Stenotrophomonas maltophilia (Sm), Staphylococcus aureus (Sa), Micrococcus luteus (Ml), Serratia marcescens (S. mar), Escherichia coli (E. coli) and anti-urease activity was performed by Indophenol method. Structures confirmed by IR, 1HNMR and 13CNMR spectroscopy. Results: Compounds showed varying degrees of antibacterial effects. Schiff bases A2 and A8 exhibited potent urease inhibition activity with Ki values 0.2754 and 0.2908 μM, respectively and their binding affinity was calculated as greater than the standard drug. Conclusion: Derivatives of amikacin with aromatic rings were more active antibacterials than those with an aliphatic side chain. The potent anti-urease activity has been recorded for compounds A2 and A8. Therefore, they may serve as lead compounds in the discovery of Helicobacter pylori Urease inhibitors.