Title : Deep drug discovery of mac domain of SARS-CoV-2 (WT) spike inhibitors: Utilizing experimental ACE2 inhibition TR-FRET assay screening and molecular dynamic simulations and free energy calculations
Abstract:
SARS-CoV-2 exploits the homotrimer transmembrane Spike glycoproteins (S protein) during host cell invasion. Omicron, delta, and prototype SARS-CoV-2 receptor-binding domain show similar binding strength to hACE2 (Angiotensin-Converting Enzyme 2). Here we utilized multi-ligand virtual screening to identify small molecule inhibitors for their efficacy against SARS?CoV?2 virus using quantum Docking, pseudovirus ACE2 Inhibition TR-FRET Assay Screening, and Molecular Dynamic simulations (MDS). 350-thousand compounds were screened against the macrodomain of non-structural protein 3 of SARS-CoV-2. Using TR- FRET Assay, we filtered out two of 10 compounds that had no reported activity in in-vitro screen against Spike S1: ACE2 binding assay. Percentage Inhibition at 30 µM was found to be 79% for “Compound F1877-0839” and 69% for “Compound F0470-0003”. This first of its kind study identified “FILLY” pocket in macrodomains. Our 200 ns MDS revealed stable binding poses of both leads. They can be used for further development of preclinical candidates.
Keywords: SARS-CoV-2, Pseudovirus ACE2 Inhibition, COVID-19 Drug, entry inhibitors, virtual screening, Molecular Dynamic Simulations, MMGBSA calculation
