Exploring the disruption of SARS-CoV-2 RBD binding to hACE2

Camryn Carter; Justin Airas; Haley Gladden; Bill R Miller 3rd; Carol A Parish

doi:10.3389/fchem.2023.1276760

Exploring the disruption of SARS-CoV-2 RBD binding to hACE2

Front Chem. 2023 Oct 24:11:1276760. doi: 10.3389/fchem.2023.1276760. eCollection 2023.

Authors

Camryn Carter¹, Justin Airas¹, Haley Gladden¹, Bill R Miller 3rd², Carol A Parish¹

Affiliations

¹ Department of Chemistry, Gottwald Center for the Sciences, University of Richmond, Richmond, VA, United States.
² Department of Chemistry, Truman State University, Kirksville, MO, United States.

Abstract

The COVID-19 pandemic was declared due to the spread of the novel coronavirus, SARS-CoV-2. Viral infection is caused by the interaction between the SARS-CoV-2 receptor binding domain (RBD) and the human ACE2 receptor (hACE2). Previous computational studies have identified repurposed small molecules that target the RBD, but very few have screened drugs in the RBD-hACE2 interface. When studies focus solely on the binding affinity between the drug and the RBD, they ignore the effect of hACE2, resulting in an incomplete analysis. We screened ACE inhibitors and previously identified SARS-CoV-2 inhibitors for binding to the RBD-hACE2 interface, and then conducted 500 ns of unrestrained molecular dynamics (MD) simulations of fosinopril, fosinoprilat, lisinopril, emodin, diquafosol, and physcion bound to the interface to assess the binding characteristics of these ligands. Based on MM-GBSA analysis, all six ligands bind favorably in the interface and inhibit the RBD-hACE2 interaction. However, when we repeat our simulation by first binding the drug to the RBD before interacting with hACE2, we find that fosinopril, fosinoprilat, and lisinopril result in a strongly interacting trimeric complex (RBD-drug-hACE2). Hydrogen bonding and pairwise decomposition analyses further suggest that fosinopril is the best RBD inhibitor. However, when lisinopril is bound, it stabilizes the trimeric complex and, therefore, is not an ideal potential drug candidate. Overall, these results reveal important atomistic interactions critical to the binding of the RBD to hACE2 and highlight the significance of including all protein partners in the evaluation of a potential drug candidate.

Keywords: ACE inhibitors; COVID-19; MM-GBSA; SARS-CoV-2; human ACE2 receptor; molecular dynamics; receptor binding domain; repurposed drugs.

Grants and funding

The authors declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by awards from the National Science Foundation (CP: CHE-1800014). CP acknowledges the Donors of the American Chemical Society Petroleum Research Fund and the Thomas F. and Kate Miller Jeffress Memorial Trust for partial support of this work. CP also acknowledges support from the Camille and Henry Dreyfus Foundation through receipt of a Henry Dreyfus Teacher-Scholar Award. CC acknowledges support from the Arnold and Mabel Beckman Foundation through receipt of Beckman Scholar awards. CC and JA acknowledge summer support from the Puryear-Topham-Pierce-Gupton endowment from the Department of Chemistry at the University of Richmond. CC, HG, and JA acknowledge summer support from the University of Richmond Integrated and Inclusive Science program, and the Arts and Sciences Undergraduate Research Committee. Computational support was provided by George Flanagin and computational resources were provided, in part, by the MERCURY supercomputer consortium under NSF grants CHE-0116435 and CHE-0521063.