Drug and Drug-like Molecule Binding to Interface of SARS-CoV-2 Sprotein:human ACE2 Complex: A Density Functional Theory Study

SARS-CoV-2 S-protein:human ACE2 complex models. QM-MM optimized active site model of SARS-CoV-2 S-protein:human ACE2 interface. ONIOM(B3LYP/6-31G*:PM7) method is the chosen QM-MM method. DFT B3LYP/6-31G* level data on energetics is reported for drug-receptor interaction. Several FDA approved drugs and traditional herbal isolates are modelled. Used Gaussian16 to model the systems. The interface cavity of SARS-CoV-2 S-protein:human ACE2 complex ( M ) for ligand ( L ) binding is modelled using a two layer ONIOM(B3LYP/6-31G*:PM7) method for sixteen traditional herbal isolates (THI) and nineteen drugs. The binding energy (E b ) of ML complexes increased with increase in dipole moment of L s. E b better than -80.0 kcal/mol is observed for digallic acid and adenosine 3',5'-bisphosphate whereas myricetin, glucogallin, sapropterin, tetrahydrobiopterin, protirelin and fidarestat showed E b better than -60.0 kcal/mol. Multiple noncovalent interactions emanating from arginine, histidine, tyrosine, lysine, carboxylate and amide units (total around 6 - 8) of L , S-protein and ACE2 receptors provide the high binding energy. The sugar substitute aspartame modified with myricetin unit showed the best E b -91.7 kcal/mol. ONIOM-linked DFT study is effective, affordable and reliable for a quantum chemical rational design approach to model drug-receptor binding process for COVID-19 drug development which sheds light upon the noncovalent binding features of receptor cavity.