tetano
Editor, Senior Moderator
Eur J Pharm Sci
. 2021 Mar 25;105820.
doi: 10.1016/j.ejps.2021.105820. Online ahead of print.
In-silico screening for identification of potential inhibitors against SARS-CoV-2 transmembrane serine protease 2 (TMPRSS2)
Sagar Barge[SUP] 1 [/SUP], Dhananjay Jade[SUP] 2 [/SUP], Gokul Gosavi[SUP] 3 [/SUP], Narayan Chandra Talukdar[SUP] 4 [/SUP], Jagat Borah[SUP] 5 [/SUP]
Affiliations
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[SUP]st[/SUP] 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[SUP]nd[/SUP] 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.
Keywords: Drug repositioning; Molecular Docking; SARS-CoV-2; Transmembrane serine protease 2; Virtual screening.
. 2021 Mar 25;105820.
doi: 10.1016/j.ejps.2021.105820. Online ahead of print.
In-silico screening for identification of potential inhibitors against SARS-CoV-2 transmembrane serine protease 2 (TMPRSS2)
Sagar Barge[SUP] 1 [/SUP], Dhananjay Jade[SUP] 2 [/SUP], Gokul Gosavi[SUP] 3 [/SUP], Narayan Chandra Talukdar[SUP] 4 [/SUP], Jagat Borah[SUP] 5 [/SUP]
Affiliations
- PMID: 33775827
- DOI: 10.1016/j.ejps.2021.105820
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[SUP]st[/SUP] 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[SUP]nd[/SUP] 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.
Keywords: Drug repositioning; Molecular Docking; SARS-CoV-2; Transmembrane serine protease 2; Virtual screening.