Identification and prioritization of potential therapeutic molecules against LpxA from Acinetobacter baumannii - A computational study

Rameez Jabeer Khan; Ekampreet Singh; Rajat Kumar Jha; Ankit Kumar; Saurabh Kumar Bhati; Mahrukh Parveez Zia; Monika Jain; Rashmi Prabha Singh; Jayaraman Muthukumaran; Amit Kumar Singh

doi:10.1016/j.crstbi.2023.100096

Identification and prioritization of potential therapeutic molecules against LpxA from Acinetobacter baumannii - A computational study

Curr Res Struct Biol. 2023 Feb 15:5:100096. doi: 10.1016/j.crstbi.2023.100096. eCollection 2023.

Affiliations

¹ Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, U.P, India.
² Department of Biotechnology, IILM College of Engineering & Technology, Greater Noida, U.P, India.

Abstract

A. baumannii is a ubiquitously found gram-negative, multi-drug resistant bacterial species from the ESKAPE family of pathogens known to be the causative agent for hospital-acquired infections such as pneumonia, meningitis, endocarditis, septicaemia and urinary tract infections. A. baumannii is implicated as a contributor to bloodstream infections in approximately 2% of all worldwide infections. Hence, exploring novel therapeutic agents against the bacterium is essential. LpxA or UDP-N-acetylglucosamine acetyltransferase is an essential enzyme important in Lipid A biosynthesis which catalyses the reversible transfer of an acetyl group on the glucosamine 3-OH of the UDP-GlcNAc which is a crucial step in the biosynthesis of the protective Lipopolysaccharides (LPS) layer of the bacteria which upon disruption can lead to the elimination of the bacterium which delineates LpxA as an appreciable drug target from A. baumannii. The present study performs high throughput virtual screening of LpxA against the enamine-HTSC-large-molecule library and performs toxicity and ADME screening to identify the three promising lead molecules subjected to molecular dynamics simulations. Global and essential dynamics analysis of LpxA and its complexes along with FEL and MM/PBSA based binding free energy delineate Z367461724 and Z219244584 as potential inhibitors against LpxA from A. baumannii.

Keywords: Free energy landscape; Global and essential dynamics; LpxA; MM/PBSA; Molecular dynamics simulations.