Discovery of novel TMPRSS2 inhibitors for COVID-19 using in silico fragment-based drug design, molecular docking, molecular dynamics, and quantum mechanics studies

Abdulrahim A Alzain; Fatima A Elbadwi; Fatima O Alsamani

doi:10.1016/j.imu.2022.100870

Discovery of novel TMPRSS2 inhibitors for COVID-19 using in silico fragment-based drug design, molecular docking, molecular dynamics, and quantum mechanics studies

Inform Med Unlocked. 2022:29:100870. doi: 10.1016/j.imu.2022.100870. Epub 2022 Feb 2.

Authors

Abdulrahim A Alzain¹, Fatima A Elbadwi¹, Fatima O Alsamani¹

Affiliation

¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Gezira, Sudan.

Abstract

The global expansion of COVID-19 and the mutations of severe acute respiratory syndrome coronavirus necessitate quick development of treatment and vaccination. Because the androgen-responsive serine protease TMPRSS2 is involved in cleaving the SARS-CoV-2 spike protein allowing the virus to enter the cell, therefore, direct TMPRSS2 inhibition will inhibit virus activation and disease progression which make it an important target for drug discovery. In this study, a homology model of TMPRSS2 protein was initially developed. Then, we used the fragment-based drug design (FBDD) technique to develop effective TMPRSS2 inhibitors. Over a half-million fragments from the enamine database were screened for their binding ability to target protein, and then best-scoring fragments were linked to building new molecules with a good binding affinity. XP docking and MM-GBSA studies revealed 10 new formed molecules with docking score ≤ -14.982 kcal/mol compared to ambroxol (control) with a docking score of -6.464 kcal/mol. Finally, molecular dynamics (MD) and density functional theory (DFT) were calculated for the top 3 molecules.

Keywords: Docking; Fragment-based drug design; Homology modeling; Molecular dynamics; Quantum mechanics; SARS-CoV-2; TMPRSS2.