Issue 2, 2022

Thermodynamic and structural insights into the repurposing of drugs that bind to SARS-CoV-2 main protease

Abstract

Although researchers have been working tirelessly since the COVID-19 outbreak, so far only three drugs – remdesivir, ronapreve and molnupiravir – have been approved for use in some countries which directly target the SARS-CoV-2 virus. Given the slow pace and substantial costs of new drug discovery and development, together with the urgency of the matter, repurposing of existing drugs for the ongoing disease is an attractive proposition. In a recent study, a high-throughput X-ray crystallographic screen was performed for a selection of drugs which have been approved or are in clinical trials. Thirty-seven compounds have been identified from drug libraries all of which bind to the SARS-CoV-2 main protease (3CLpro). In the current study, we use molecular dynamics simulation and an ensemble-based free energy approach, namely, enhanced sampling of molecular dynamics with approximation of continuum solvent (ESMACS), to investigate a subset of the aforementioned compounds. The drugs studied here are highly diverse, interacting with different binding sites and/or subsites of 3CLpro. The predicted free energies are compared with experimental results wherever they are available and they are found to be in excellent agreement. Our study also provides detailed energetic insights into the nature of the associated drug–protein binding, in turn shedding light on the design and discovery of potential drugs.

Graphical abstract: Thermodynamic and structural insights into the repurposing of drugs that bind to SARS-CoV-2 main protease

Article information

Article type
Paper
Submitted
28 8 2021
Accepted
15 11 2021
First published
18 11 2021
This article is Open Access
Creative Commons BY license

Mol. Syst. Des. Eng., 2022,7, 123-131

Thermodynamic and structural insights into the repurposing of drugs that bind to SARS-CoV-2 main protease

S. Wan, A. P. Bhati, A. D. Wade, D. Alfè and P. V. Coveney, Mol. Syst. Des. Eng., 2022, 7, 123 DOI: 10.1039/D1ME00124H

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements