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

submitted on 08.10.2020, 10:24 and posted on 08.10.2020, 10:49 by CH Suresh
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 (Eb) of ML complexes increased with increase in dipole moment of Ls. Eb 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 Eb 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 Eb -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.


CSIR-NIIST funding for Covid-19 modelling


Email Address of Submitting Author


CSIR–National Institute for Interdisciplinary Science and Technology (CSIR–NIIST)



ORCID For Submitting Author


Declaration of Conflict of Interest

No conflict of interest

Version Notes

First version