Deep learning-based Drug discovery of Mac domain of SARS-CoV-2 (WT) Spike inhibitors: using experimental ACE2 Inhibition TR-FRET Assay Screening and Molecular Dynamic Simulations.

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 {micro}M 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. Abstract Image O_FIG O_LINKSMALLFIG WIDTH=178 HEIGHT=200 SRC="FIGDIR/small/512637v1_ufig1.gif" ALT="Figure 1"> View larger version (83K): org.highwire.dtl.DTLVardef@a8be27org.highwire.dtl.DTLVardef@5bff16org.highwire.dtl.DTLVardef@1c835f4org.highwire.dtl.DTLVardef@14e5438_HPS_FORMAT_FIGEXP M_FIG C_FIG In BriefIqbal et al., described a deep learning guided drug discovery, efficacy against SARS-CoV-2 Spike inhibitors: using experimental pseudovirus ACE2 Inhibition TR-FRET Assay. Our molecular dynamic simulation results were next validated a posteriori against the corresponding experimental data of identified leads with 80 percent inhibition. Moreover, this study is first of kind to identify "FILLY" pocket in macrodomains. HighlightsO_LIExperimental pseudovirus ACE2 Inhibition TR-FRET Assay and HTS lead to identification of two potential clinical leads. C_LIO_LIConformational Dynamics analysis reveal the structural stability of complexes throughout 200 ns molecular dynamic simulations. C_LIO_LIUnveiling of the impact surface charge on the Variant of Concerns C_LIO_LIDetection of conformational changes within ACE2/RBD complex C_LIO_LIWe identified the FILLY pocket in the SARS viruses. C_LI