The COVID-19 pandemic caused by SARS-CoV-2 has shown an exponential trend of infected people across the planet. Crediting its virulent nature, it becomes imperative to identify potential therapeutic agents against the deadly virus. The 3-chymotrypsin-like protease (3CLpro) is a cysteine protease which causes the proteolysis of the replicase polyproteins to generate functional proteins, which is a crucial step for viral replication and infection. Computational methods have been applied in recent studies to identify promising inhibitors against 3CLpro to inhibit the viral activity. This review provides an overview of promising drug/lead candidates identified so far against 3CLpro through various in silico approaches such as structure-based virtual screening (SBVS), ligand-based virtual screening (LBVS) and drug-repurposing/drug-reprofiling/drug-retasking. Further, the drugs have been classified according to their chemical structures or biological activity into flavonoids, peptides, terpenes, quinolines, nucleoside and nucleotide analogues, protease inhibitors, phenalene and antibiotic derivatives. These are then individually discussed based on the various structural parameters namely estimated free energy of binding (ΔG), key interacting residues, types of intermolecular interactions and structural stability of 3CLpro-ligand complexes obtained from the results of molecular dynamics (MD) simulations. The review provides comprehensive information of potential inhibitors identified through several computational methods thus far against 3CLpro from SARS-CoV-2 and provides a better understanding of their interaction patterns and dynamic states of free and ligand-bound 3CLpro structures.

Gallic acid (PubChem CID: 370) and quercetin (PubChem CID: 5280343) are major phenolic compounds in many mangrove plants that have been related to health cure. In the present study, the active fractions namely gallic acid (1) and quercetin (2) were isolated from the methanolic extract of leaves of Ceriops tagal in a Tropical mangrove ecosystem of Andaman and Nicobar Island (ANI), India. The chemical structures were determined by spectroscopic analysis: Fourier-Transform Infrared spectroscopy (FT-IR), ¹H, ¹³C Nuclear Magnetic Resonance (NMR) spectroscopy, and High-resolution mass spectrometry (HRMS). The anticancer activity of isolated compounds (1) and (2) were evaluated by in vitro assays against two human cancer cell lines namely, HeLa (Cervical) and MDA-MB231 (Breast) cancer cells revealed that IC₅₀ values of gallic acid (HeLa: 4.179197 ± 0.45 µg/ml; MDA-MB231: 80.0427 ± 0.19 µg/ml at 24 h) and quercetin (HeLa: 99.914 ± 0.18 µg/ml; MDA-MB231: 18.288382 ± 0.12 µg/ml at 24 h), respectively. Antioxidant properties of gallic acid (1) and quercetin (2) are found to be IC₅₀ value of 0.77 ± 0.41 µg/ml and 1.897 ± 0.81 µg/ml, respectively. Molecular docking results explained that gallic acid (1) and quercetin (2) showed estimated binding free energy (ΔG) of −5.4 and −6.9 kcal/mol towards drug target Bcl-B protein, respectively. The estimated inhibition constant (Ki) for these two molecules are 110 and 8.75 μM, respectively. The MD simulation additionally supported that quercetin molecule is significantly improved the structural stability of Bcl-B protein. The present study provides key insights about the importance of polyphenols, and thus leads to open the therapeutic route for anti-cancer drug discovery process. Communicated by Ramaswamy H. Sarma

The recent COVID-19 pandemic caused by SARS-CoV-2 has recorded a high number of infected people across the globe. The virulent nature of the virus makes it necessary for us to identify promising therapeutic agents in a time-sensitive manner. The current study utilises an in silico based drug repurposing approach to identify potential anti-viral drug candidates targeting non-structural protein 15 (NSP15), i.e. a uridylate specific endoribonuclease of SARS-CoV-2 which plays an indispensable role in RNA processing and viral immune evasion from the host immune system. The NSP15 protein was screened against an in-house library of 123 antiviral drugs obtained from the DrugBank database from which three promising drug candidates were identified based on their estimated binding affinities (ΔG), estimated inhibition constants (Ki), the orientation of drug molecules in the active site and the key interacting residues of NSP15. Molecular dynamics (MD) simulations were performed for the screened drug candidates in complex with NSP15 as well as the apo form of NSP15 to mimic their physiological states. Based on the stable MD simulation trajectories, the binding free energies of the screened NSP15-drug complexes were calculated using the MM/PBSA approach. Two candidate drugs, Simeprevir and Paritaprevir, achieved the lowest binding free energies for NSP15, with a value of −259.522 ± 17.579 and −154.051 ± 33.628 kJ/mol, respectively. In addition, their complexes with NSP15 also exhibited the strongest structural stabilities. Taken together, we propose that Simeprevir and Paritaprevir are promising drug candidates to inhibit NSP15 and may act as potential therapeutic agents against SARS-CoV-2. Communicated by Ramaswamy H. Sarma

This study reports the experimental and computational investigation on the binding of a common anticancer drug, gemcitabine, with the model plasma protein, bovine serum albumin (BSA). Several experimental and computational methods, such as intrinsic and synchronous fluorescence, UV-visible, and circular dichroism spectroscopies, consensus molecular docking and molecular dynamics simulation have been employed to elucidate the binding mechanism. Gemcitabine altered the UV-visible spectrum of BSA, which is a clear indication of the complex formation between them. The visual inspection of observed fluorescence quenching results at λ_ex = 280 nm and 295 nm has shown the substantial involvement of tyrosine residue, even larger than tryptophan. However, after the correction of inner filter effect of the observed data, it became clear that tyrosine has a negligible role in quenching. A 20-fold decrease in quenching constant was found in the corrected data, as compared to the observed data at λ_ex = 280 nm. There was a 1:1 weak binding between BSA and gemcitabine accompanied by dynamic quenching. The secondary structure of BSA remained almost intact in the presence of gemcitabine. The primary binding site of gemcitabine inside BSA was the drug binding site 2 or DS II, which is located in the subdomain 3 A. MD Simulation results suggested that gemcitabine doesn’t affect or deviate the structure of BSA upon interaction throughout 100 ns time period. The dominating intermolecular forces were hydrophobic forces and hydrogen bonding. A small change in the frontier molecular orbitals of gemcitabine was also observed after its binding with BSA. Communicated by Ramaswamy H. Sarma

The flavonoid based 7-hydroxy flavone (PubChem CID: 5281894; molecular formula: C₁₅H₁₀O₃) molecule has been isolated for the first time from the methanolic extract from the leaves of Avicennia officinalis L. in the tropical mangrove ecosystem of Andaman and Nicobar Islands (ANI), India. The molecular structure of bioactive compound was characterized by spectroscopic analysis, including FT-IR, ¹H, ¹³C NMR spectroscopy and ESI-HRMS and elucidated as 7-hydroxy flavone. An anticancer activity of isolated 7-hydroxy flavone was evaluated by in vitro study against two different human cancer cell lines namely, HeLa (cervical cells) and MDA-MB231 (breast cells) and they exhibited promising anticancer activity with IC₅₀ values are 22.5602 ± 0.21 µg/mL and 3.86474 ± 0.35 µg/mL, respectively. The antioxidant property of 7-hydroxy flavone at a standard concentration of 50 µg, was found to be (IC₅₀) 5.5486 ± 0.81 µg/mL. In summary, this investigation provides evidence that 7-hydroxy flavone exhibits both anticancer and antioxidant properties. Meanwhile, the antimicrobial activity ability of 7-hydroxy flavone were also evaluated using three Gram positive and two Gram negative strain exhibited no antimicrobial activities. Density-functional theory (DFT) studies confirm the structure is global minima in the PES, from the optimized geometry FMO and MESP map analyzed. Further, the molecular docking and molecular dynamics simulation studies result shows that 7-hydroxy flavone has the better binding ability with anti-apoptotic Bcl-2 protein with the estimated free energy of binding of –6.3 kcal/mol. This bioactive compound may be act as drug candidate for treating various kinds of cancers. Communicated by Ramaswamy H. Sarma