Quantum chemical studies on the binding domain of SARS-CoV-2 S-protein: human ACE2 interface complex

Abstract

A two-layer ONIOM(B3LYP/6-31G*:PM7) method is used to model the binding of several drug/drug-like molecules (L) at the SARS-CoV-2 S-protein: human ACE2 protein interface cavity. The selected molecules include a set of thirty-five ligands from the study of Smith and Smith which showed a high docking score in the range of −7.0 to −7.7 kcal/mol and another set of seven repurposing drugs, viz. favipiravir, remdesivir, EIDD, galidesivir, triazavirin, ruxolitinib, and baricitinib. The ONIOM model of the cavity (M) showed a highly polarized electron distribution along its top-to-bottom direction while Ls with lengths in the range 1.0 − 1.5 nm fitted well inside the cavity in a head-to-tail fashion to yield ML complexes. The ligands showed a large variation in the ONIOM-level binding energy (E_b), in the range −2.7 to −85.4 kcal/mol. The E_b of ML complexes better than −40.0 kcal/mol is observed for myricetin, fidarestat, protirelin, m-digallic acid, glucogallin, benserazide hydrochlorideseradie, remdesivir, tazobactum, sapropterin, nitrofurantoin, quinonoid, pyruvic acid calcium isoniazid, and aspartame, and among them the highest E_b −85.4 kcal/mol is observed for myricetin. A hydroxy substitution is suggested for the phenyl ring of aspartame to improve its binding behavior at the cavity, and the resulting ligand 43 showed the best E_b −84.5 kcal/mol. The ONIOM-level study is found to be effective for the interpretation of the noncovalent interactions resulting from residues such as arginine, histidine, tyrosine, lysine, carboxylate, and amide moieties in the active site and suggests rational design strategies for COVID-19 drug development.

Communicated by Ramaswamy H. Sarma

A quantum chemical treatment of the noncovalently-bonded drug and drug-like molecules at the interface of SARS-CoV2: human ACE2 receptor is described. It predicts that myricetin, fidarestat, protirelin, m-digallic acid, glucogallin, benserazide hydrochlorideseradie, remdesivir, tazobactum, sapropterin, nitrofurantoin, quinonoid, pyruvic acid calcium isoniazid, and aspartame have high binding affinity at the interface and also suggests a design strategy to modify aspartame for improved binding affinity.

Keywords:

• ONIOM
• Molecular docking
• DFT
• COVID-19
• S-protein
• ACE2 receptor
• MESP

Acknowledgments

The research is supported by the CSIR-NIIST COVID-19 project fund and DST-SERB, India, through the project GAP160439. We also acknowledge the support from the IT laboratory of CSIR-NIIST.

Disclosure statement

There are no conflicts to declare.

Additional information

Funding

This work is funded by DST-SERB only.