Identification of potent inhibitors against transmembrane serine protease 2 for developing therapeutics against SARS-CoV-2.

In viral binding and entry, the Spike(S) protein of SARS-CoV-2 uses transmembrane serine protease 2 (TMPRSS2) for priming to cleavage themselves. In this study, we have screened 'drug-like' 7476 ligands and found that over thirty ligands can effectively inhibit the TMPRSS-2 better than the control ligand. Finally, the three best drug agents L1, L2, and L6 were selected according to their average binding affinities and fitting score. These ligands interact with Asp435, Cys437, Ser436, Trp461, and Cys465 amino acid residues. The three best candidates and a reported drug Nafamostat mesylate (NAM) were selected to run 250 ns molecular dynamics (MD) simulations. Various properties of ligand-protein interactions obtained from MD simulation such as bonds, angle, dihedral, planarity, coulomb, and van der Waals (VdW) were used for principal component analysis (PCA) calculation. PCA discloses the evidence of the structural similarities to the corresponding complexes of L1, L2, and L6 with the complex of TMPRSS2(TM) and Nafamostat mesylate (TM-NAM). Moreover, Quantitative structure-activity relationship (QSAR) pattern recognition was generated using PCA for the investigation of structural similarities among the selected ligands. Multiple Linear Regression (MLR) model was built to predict the binding energy compared to the binding energy obtained from molecular docking. The MLR regression model reveals an accuracy of 80% for the prediction of the binding energy of ligands. ADMET analysis demonstrates that these drug agents are appeared to be safer inhibitors. These three ligands can be used as potential inhibitors against the TMPRSS2.Communicated by Ramaswamy H. Sarma.

Remdesivir analogs against SARS-CoV-2 RNA-dependent RNA polymerase.

The COVID-19 pandemic has already taken many lives but is still continuing its spread and exerting jeopardizing effects. This study is aimed to find the most potent ligands from 703 analogs of remdesivir against RNA-dependent RNA polymerase (RdRp) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus . RdRp is a major part of a multi-subunit transcription complex of the virus, which is essential for viral replication. In clinical trials, it has been found that remdesivir is effective to inhibit viral replication in Ebola and in primary human lung cell cultures; it effectively impedes replication of a broad-spectrum pre-pandemic bat coronaviruses and epidemic human coronaviruses. After virtual screening, 30 most potent ligands and remdesivir were modified with triphosphate. Quantum mechanics-based quantitative structure-activity relationship envisages the binding energy for ligands applying partial least square (PLS) regression. PLS regression remarkably predicts the binding energy of the effective ligands with an accuracy of 80% compared to the value attained from molecular docking. Two ligands (L4:58059550 and L28:126719083), which have more interactions with the target protein than the other ligands including standard remdesivir triphosphate, were selected for further analysis. Molecular dynamics simulation is done to assess the stability and dynamic nature of the drug-protein complex. Binding-free energy results via PRODIGY server and molecular mechanics/Poisson-Boltzmann surface area method depict that the potential and solvation energies play a crucial role. Considering all computational analysis, we recommend the best remdesivir analogs can be utilized for efficacy test through in vitro and in vivo trials against SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

Ternary complexes of vanadium(IV) and titanium(IV) of Schiff bases as primary ligand: Synthesis, spectral characterization, biomedical applications, and molecular docking with SARS-CoV-2 Mpro

Ternary complexes of vanadium(IV) and titanium(IV) containing macrocyclic chelate ring were synthesized from dibasic tetra-dentate Schiff bases as primary (LH2) and succinic acid (SA) as secondary ligand. Their stable formation was confirmed on the basis of spectro-analytical evidences and octahedral geometry has been proposed for mononuclear ternary complexes, [M(L)SA] (M = Ti4+, V4+). The proposed structure of the complexes has been optimized by quantum mechanical calculations. Some of the complexes have good antioxidant property and considerable inhibition capacity against selected pathogenic microorganisms. Molecular docking of a ligand against SARS-CoV-2 main protease (6 LU7) revealed binding affinity comparable to chloroquine used as standard. The ADMET analysis showed that it is noncarcinogenic and less toxic indicating as good candidate against SARS-CoV-2 infection.

Investigating the binding affinity, interaction, and structure-activity-relationship of 76 prescription antiviral drugs targeting RdRp and Mpro of SARS-CoV-2.

SARS-CoV-2 virus outbreak poses a major threat to humans worldwide due to its highly contagious nature. In this study, molecular docking, molecular dynamics, and structure-activity relationship are employed to assess the binding affinity and interaction of 76 prescription drugs against RNA dependent RNA polymerase (RdRp) and Main Protease (Mpro) of SARS-CoV-2. The RNA-dependent RNA polymerase is a vital enzyme of coronavirus replication/transcription complex whereas the main protease acts on the proteolysis of replicase polyproteins. Among 76 prescription antiviral drugs, four drugs (Raltegravir, Simeprevir, Cobicistat, and Daclatasvir) that are previously used for human immunodeficiency virus (HIV), hepatitis C virus (HCV), Ebola, and Marburg virus show higher binding energy and strong interaction with active sites of the receptor proteins. To explore the dynamic nature of the interaction, 100 ns molecular dynamics (MD) simulation is performed on the selected protein-drug complexes and apo-protein. Binding free energy of the selected drugs is performed by MM/PBSA. Besides docking and dynamics, partial least square (PLS) regression method is applied for the quantitative structure activity relationship to generate and predict the binding energy for drugs. PLS regression satisfactorily predicts the binding energy of the effective antiviral drugs compared to binding energy achieved from molecular docking with a precision of 85%. This study highly recommends researchers to screen these potential drugs in vitro and in vivo against SARS-CoV-2 for further validation of utility.