Your browser doesn't support javascript.
Estimating the binding energetics of reversible covalent inhibitors of the SARS-CoV-2 main protease: an in silico study.
Awoonor-Williams, Ernest.
  • Awoonor-Williams E; Department of Chemistry, Memorial University of Newfoundland, St. John's, NL, A1B 3X9, Canada. esaw83@mun.ca.
Phys Chem Chem Phys ; 24(38): 23391-23401, 2022 Oct 05.
Article in English | MEDLINE | ID: covidwho-2036938
ABSTRACT
The main protease (Mpro) of the SARS-CoV-2 virus is an attractive therapeutic target for developing antivirals to combat COVID-19. Mpro is essential for the replication cycle of the SARS-CoV-2 virus, so inhibiting Mpro blocks a vital piece of the cell replication machinery of the virus. A promising strategy to disrupt the viral replication cycle is to design inhibitors that bind to the active site cysteine (Cys145) of the Mpro. Cysteine targeted covalent inhibitors are gaining traction in drug discovery owing to the benefits of improved potency and extended drug-target engagement. An interesting aspect of these inhibitors is that they can be chemically tuned to form a covalent, but reversible bond, with their targets of interest. Several small-molecule cysteine-targeting covalent inhibitors of the Mpro have been discovered-some of which are currently undergoing evaluation in early phase human clinical trials. Understanding the binding energetics of these inhibitors could provide new insights to facilitate the design of potential drug candidates against COVID-19. Motivated by this, we employed rigorous absolute binding free energy calculations and hybrid quantum mechanical/molecular mechanical (QM/MM) calculations to estimate the energetics of binding of some promising reversible covalent inhibitors of the Mpro. We find that the inclusion of enhanced sampling techniques such as replica-exchange algorithm in binding free energy calculations can improve the convergence of predicted non-covalent binding free energy estimates of inhibitors binding to the Mpro target. In addition, our results indicate that binding free energy calculations coupled with multiscale simulations can be a useful approach to employ in ranking covalent inhibitors to their targets. This approach may be valuable in prioritizing and refining covalent inhibitor compounds for lead discovery efforts against COVID-19 and other coronavirus infections.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Type of study: Experimental Studies / Prognostic study Limits: Humans Language: English Journal: Phys Chem Chem Phys Journal subject: Biophysics / Chemistry Year: 2022 Document Type: Article Affiliation country: D2cp03080b

Similar

MEDLINE

...
LILACS

LIS


Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Type of study: Experimental Studies / Prognostic study Limits: Humans Language: English Journal: Phys Chem Chem Phys Journal subject: Biophysics / Chemistry Year: 2022 Document Type: Article Affiliation country: D2cp03080b