Predicting antibiotic resistance in complex protein targets using alchemical free energy methods

Bibliographische Detailangaben
Veröffentlicht in:	Journal of computational chemistry. - 1984. - 43(2022), 26 vom: 05. Okt., Seite 1771-1782
1. Verfasser:	Brankin, Alice E (VerfasserIn)
Weitere Verfasser:	Fowler, Philip W
Format:	Online-Aufsatz
Sprache:	English
Veröffentlicht:	2022
Zugriff auf das übergeordnete Werk:	Journal of computational chemistry
Schlagworte:	Journal Article Research Support, Non-U.S. Gov't alchemical free energy methods antibiotic resistance molecular dynamics relative binding free energy calculations tuberculosis DNA Gyrase EC 5.99.1.3 Moxifloxacin U188XYD42P

Beschreibung
Zusammenfassung:	© 2022 The Authors. Journal of Computational Chemistry published by Wiley Periodicals LLC. Drug resistant Mycobacterium tuberculosis, which mostly results from single nucleotide polymorphisms in antibiotic target genes, poses a major threat to tuberculosis treatment outcomes. Relative binding free energy (RBFE) calculations can rapidly predict the effects of mutations, but this approach has not been tested on large, complex proteins. We use RBFE calculations to predict the effects of M. tuberculosis RNA polymerase and DNA gyrase mutations on rifampicin and moxifloxacin susceptibility respectively. These mutations encompass a range of amino acid substitutions with known effects and include large steric perturbations and charged moieties. We find that moderate numbers (n = 3-15) of short RBFE calculations can predict resistance in cases where the mutation results in a large change in the binding free energy. We show that the method lacks discrimination in cases with either a small change in energy or that involve charged amino acids, and we investigate how these calculation errors may be decreased
Beschreibung:	Date Completed 13.09.2022 Date Revised 17.05.2024 published: Print-Electronic Citation Status MEDLINE
ISSN:	1096-987X
DOI:	10.1002/jcc.26979