Integrated bioinformatics-cheminformatics approach toward locating pseudo-potential antiviral marine alkaloids against SARS-CoV-2-Mpro.

The emergence of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) with the most contagious variants, alpha (B.1.1.7), beta (B.1.351), delta (B.1.617.2), and Omicron (B.1.1.529) has continuously added a higher number of morbidity and mortality, globally. The present integrated bioinformatics-cheminformatics approach was employed to locate potent antiviral marine alkaloids that could be used against SARS-CoV-2. Initially, 57 antiviral marine alkaloids and two repurposing drugs were selected from an extensive literature review. Then, the putative target enzyme SARS-CoV-2 main protease (SARS-CoV-2-Mpro) was retrieved from the protein data bank and carried out a virtual screening-cum-molecular docking study with all candidates using PyRx 0.8 and AutoDock 4.2 software. Further, the molecular dynamics (MD) simulation of the two most potential alkaloids and a drug docking complex at 100 ns (with two ligand topology files from PRODRG and ATB server, separately), the molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) free energy, and contributions of entropy were investigated. Then, the physicochemical-toxicity-pharmacokinetics-drug-likeness profiles, the frontier molecular orbitals energies (highest occupied molecular orbital, lowest unoccupied molecular orbital, and ΔE), and structural-activity relationship were assessed and analyzed. Based on binding energy, 8-hydroxymanzamine (-10.5 kcal/mol) and manzamine A (-10.1 kcal/mol) from all alkaloids with darunavir (-7.9 kcal/mol) and lopinavir (-7.4 kcal/mol) against SARS-CoV-2-Mpro were recorded. The MD simulation (RMSD, RMSF, Rg, H-bond, MM/PBSA binding energy) illustrated that the 8-hydroxymanzamine exhibits a static thermodynamic feature than the other two complexes. The predicted physicochemical, toxicity, pharmacokinetics, and drug-likeness profiles also revealed that the 8-hydroxymanzamine could be used as a potential lead candidate individually and/or synergistically with darunavir or lopinavir to combat SARS-CoV-2 infection after some pharmacological validation.

Quinoline heterocyclic containing plant and marine candidates against drug-resistant Mycobacterium tuberculosis: A systematic drug-ability investigation.

Today, tuberculosis (TB) caused by the acid-fast bacilli, Mycobacterium tuberculosis (Mtb) is the most infectious killer disease globally with high morbidity and mortality rates. The rapid development of multi-drug-resistant (MDR) strains via intrinsic (efflux pumps) and acquired (biological mutations) mechanisms reduce the efficacy of applied anti-TB regimens. Nevertheless, only bedaquiline (BDQ) and pretomanid (PMD) were added to anti-TB therapy in the last decade. The existing anti-TB drugs also exhibited cytotoxicity and hepatotoxicity from long-term treatment. Thus, exploring or developing potential and less toxic anti-TB candidates, preferably natural-based candidates, is the call of the day. At present, 'quinoline' could be considered one of the versatile scaffolds presented in most mainstream medicines from comprehensive drug reports. Notably, BDQ with two clinically evaluating anti-TB candidates, TBJA-587 and DC-159a was motivated for utilizing quinoline heterocycles. Accordingly, we have selected 65 natural quinoline heterocycles bearing potential anti-TB agents (40 plant-derived and 25 marine-derived) within MIC value ≤ 50 µg/mL from an extensive literature search. Briefly, source, drug chemistry, structural activity relationship, prior pharmacokinetics profiles with drug-ability, toxicity, and hierarchical clustering analysis using various computational tools to identify the most 'drug-able lead' candidate is the uniqueness of the review. From extensive drug analysis, tetrandrine, 2'-nortiliacorinine, tiliacorine, globospiramine, evocarpine, allocuspareine from plant sources, and ecteinascidin 770, 6-hydroxymanzamine E, (-)-8-hydroxymanzamine A, ecteinascidin 786, manzamine F from marine sources are the most potential-cum-drug-able anti-TB candidates. We hope the systematic and critical drug analyses on quinoline-bearing natural anti-TB candidates are helpful to design potential-cum-less toxic anti-TB drugs in the future.

Anti-HIV-drug and phyto-flavonoid combination against SARS-CoV-2: a molecular docking-simulation base assessment.

At the health emergence, no such potent prophylactic therapy is available to control the deadly emerged Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). However, existing antiviral, anti-inflammatory, antimalarial drugs is the only option against SARS-CoV-2, but it may be harmful to patients without more clinical evidence. As an alternative solution, we proposed a newer hypothesis using the selective 10 potent anti-HIV drugs and flavonoid class of phytochemicals from previous reports to use in combination against SARS-CoV-2. Primarily, 10 anti-HIV protease inhibitor drugs and 10 phyto-flavonoids as ligands in molecular docking study against the putative target, the SARS-CoV-2-main protease (Mpro) ID: 6Y2E), as an essential enzyme in viral genome replication. According to molecular docking and drug-ability scores of each ligand, the anti-HIV drug, the darunavir (with a docking score, -10.25 kcal/mol and drug-likeness rating, 0.60) and the quercetin-3-rhamnoside (with a docking score, -10.90 kcal/mol and drug-likeness rating, 0.82) were selected for further analysis in combined effect. Perceptibly, the combined 'anti-HIV drug and phyto-flavonoid' docking complex has actively interacted with eight strong H-bonds with stability, briefly elucidated through RMRD-, RMSF- Rg-plots and MM/PBSA-binding energy calculation during 100 ns than the individual against SARS-CoV-2-Mpro. Thus, the 'anti-HIV-drug-phyto-flavonoid' combination therapy could be used against SARS-CoV-2 after some experimental validation.Communicated by Ramaswamy H. Sarma.