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

Area of Science:

• * Computational drug discovery and molecular modeling.
• * Virology and infectious disease research.
• * Biochemistry and molecular dynamics simulations.

Background:

• * The COVID-19 pandemic is caused by SARS-CoV-2, which infects cells via the interaction between its receptor binding domain (RBD) and the human ACE2 (hACE2) receptor.
• * Existing drug screening often focuses on the RBD alone, neglecting the crucial RBD-hACE2 interface.
• * A comprehensive analysis requires evaluating drug interactions with both RBD and hACE2.

Purpose of the Study:

• * To screen potential drug candidates targeting the RBD-hACE2 interface.
• * To assess the binding characteristics and inhibitory potential of selected ligands using molecular dynamics simulations.
• * To elucidate the atomistic interactions governing the RBD-hACE2 binding and inhibition.

Main Methods:

• * Screening of ACE inhibitors and known SARS-CoV-2 inhibitors for binding to the RBD-hACE2 interface.
• * Conducting 500 ns unrestrained molecular dynamics (MD) simulations for six selected ligands (fosinopril, fosinoprilat, lisinopril, emodin, diquafosol, physcion).
• * Utilizing MM-GBSA, hydrogen bonding, and pairwise decomposition analyses to evaluate binding affinity and interactions.

Main Results:

• * All six tested ligands demonstrated favorable binding at the RBD-hACE2 interface, inhibiting the interaction.
• * Fosinopril, fosinoprilat, and lisinopril formed stable trimeric complexes (RBD-drug-hACE2) in simulations.
• * Fosinopril exhibited the strongest inhibitory effect on the RBD, while lisinopril stabilized the trimeric complex, deeming it less ideal.

Conclusions:

• * The study identified key atomistic interactions crucial for RBD-hACE2 binding.
• * Fosinopril emerged as a promising candidate for inhibiting SARS-CoV-2 entry.
• * The findings underscore the importance of evaluating drug candidates within the context of all interacting protein partners for accurate assessment.