Prediction of Binding Pose and Affinity of SARS-CoV-2 Main Protease and Repositioned Drugs by Combining Docking, Molecular Dynamics, and Fragment Molecular Orbital Calculations

25 July 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

COVID-19 remains a global pandemic, necessitating the urgent development of more effective therapeutics. By combining molecular docking, molecular dynamics (MD), and fragment molecular orbital (FMO) calculations, the binding structure and properties with Mpro were predicted for Nelfinavir (NLF), which was identified as a candidate compound through drug repositioning targeting the Main Protease (Mpro) produced by the causative virus, SARS-CoV-2. For the four docking poses selected by scoring using FMO energy, 100 structures each from the MD trajectory were sampled, and FMO calculations were performed and ranked based on binding energy. Besides the interaction between NLF and each Mpro residue, the desolvation effect of the pocket affected the ranking order. Furthermore, we identified several residues important in ligand recognition, including Glu47, Asp48, Glu166, Asp187, and Gln189, all of which interacted strongly with NLF. Asn142 was mentioned as a residue with hydrogen bonds or CH/π interaction with NLF; however, it was considered a transient interacting residue because of its unstable structure. Moreover, the tert-butyl group of NLF had no interaction with Mpro. Identifying weak interactions provides candidates for substituting ligand functional groups and important suggestions for drug discovery using drug repositioning. Our approach provides a new guideline for structure-based drug design starting from a candidate compound whose complex crystal structure has not been obtained.

Keywords

fragment molecular orbital method
SARS-CoV-2 main protease
drug repositioning
drug designn
intermolecular interaction

Supplementary materials

Title
Description
Actions
Title
supporting materials
Description
supporting figures and tables
Actions

Comments

Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.
Comment number 1, Kaori Fukuzawa: Jul 15, 2024, 12:12

This article has been published; https://doi.org/10.1021/acs.jpcb.3c05564