In-silico screening for identification of potential inhibitors against SARS-CoV-2 transmembrane serine protease 2 (TMPRSS2)

Abstract

A new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a respiratory infection out broke in December 2019 in Wuhan, Hubei province, China, resulted in pandemic conditions worldwide. COVID-19 spread swiftly around the world over with an alert of an emergency for an adequate drug. Therefore, in this research, we repurposed the FDA-approved medicines to find the prominent drug used to cure the COVID infected patients. We performed homology modeling of the transmembrane serine protease 2 (TMPRSS2), responsible for the viral entry. The prediction of the transmembrane region and the Conserved Domain in TMPRSS2 protein was made for docking. 4182 FDA-approved compounds from the ZINC database were downloaded and used for the calculation of physicochemical properties. Two thousand eight hundred fifteen screened compounds were used for molecular docking against the modelled protein structure. From which top hit compounds based on binding energy were extracted. At 1 st site pose, ZINC3830554 showed the highest binding energy -12.91kcal/mol by forming Salt Bridge at LYS143, Hydrogen bond at ALA8, VAL45, HIS47, SER142, ASN277, ASN359, and TRP363. The hydrophobic Interactions at PHE3, LEU4, ALA7, ALA8, ALA139, PRO197, and PHE266. In the 2 nd site pose, ZINC203686879 shows the highest binding energy (-12.56 kcal/mol) and forms a hydrophobic interaction with VAL187, VAL189, HIS205, LYS301, GLN347, TRP370 and hydrogen bond was at GLY300, THR302, GLN347, SER350 residues. These hit compounds were subjected to stability checks between the protein-ligand complex through the dynamics simulation (MD), and binding free energy was calculated through the Molecular Mechanics energies combined with Poisson-Boltzmann (MM/PBSA) method. We hope that hit compounds would be an efficient inhibitor that can block the TMPRSS2 activity and resist the entry of the SARS-CoV-2 virus into targeted human cells by reducing the virus's infectivity and transmissibility.

Repurposing of Drugs Against Mutated Strain of Eurasian Avian Like H1N1 (EA H1N1) Swine Flu Virus, Genotype 4(G4) Virus

“…The stability of the built model was analysed by the Structure analysis and verification server, SAVES v 6.0 (https://saves.mbi.ucla.edu/). The quality of each of the modeled protein was verified by the ERRAT score calculated in SAVES, where the value depicted that the non-bonded interactions of each models lied within a reasonable normal range(Barge et al, 2021)The overall stereochemical quality and overall and residue by residue geometry of the build models are analysed by the Procheck, wherein the Ramachandran plot were analysed for each models. The Ramachandran plot is basically used to check the protein conformation and reliability of φ and ψ angles in the backbone of amino acid residues in protein(Barge et al, 2021; Rakib et al, 2021)…”

Identification of some dietary flavonoids as potential inhibitors of TMPRSS2 through protein–ligand interaction studies and binding free energy calculations

“…The coronavirus disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has emerged as a global pandemic and is continuing as a threat to human beings [ 1 ]. SARS-CoV-2 is a beta coronavirus similar to SARS-CoV and MERS viruses.…”

“…TMPRSS2 breaks the viral S-protein at the right upstream of fusion peptide and results in membrane fusion. This points out the importance of inhibiting TMPRSS2 to avoid the host cell entry of SARS-CoV-2 virus [ 1 ]. Another reason which makes TMPRSS2 a promising target is the fact that it is a human protease, thereby this eliminates the problem of causing drug resistance like viral protein targets [ 2 ].…”

Target identification for repurposed drugs active against SARS-CoV-2 via high-throughput inverse docking

“…Here we report an improvement to INDO that aims specifically to identify the potential targets of repurposed drugs with experimentally proved activity against SARS-CoV-2. This strategy is distinct from theoretical drug database screening [29][30][31][32] because we restrict our pool of drugs to those already shown by consensus of two or more experimental HTS studies to have anti-SARS-CoV-2 activity. From a joint dataset built from three independent HTS assays that measure inhibition of infection of cultured cells [20][21][22], we built a ligand set from the top 25% most active compounds in two out of the three studies, comprising 158 distinct compounds.…”