Elucidating specific interactions for designing novel pyrrolamide derivatives as potential GyrB inhibitors based on ab initio fragment molecular orbital calculations

Paptawan Thongdee; Yoshinobu Nagura; Haruna Sabishiro; Naruedon Phusi; Darunee Sukchit; Pharit Kamsri; Auradee Punkvang; Khomson Suttisintong; Pornpan Pungpo; Noriyuki Kurita

doi:10.1080/07391102.2023.2291178

Elucidating specific interactions for designing novel pyrrolamide derivatives as potential GyrB inhibitors based on ab initio fragment molecular orbital calculations

J Biomol Struct Dyn. 2023 Dec 8:1-14. doi: 10.1080/07391102.2023.2291178. Online ahead of print.

Affiliations

¹ Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ubon Ratchathani University, Ubon Ratchathani, Thailand.
² Department of Computer Science and Engineering, Toyohashi University of Technology, Toyohashi, Aichi, Japan.
³ Division of Chemistry, Faculty of Science, Nakhon Phanom University, Nakhon Phanom, Thailand.
⁴ National Nanotechnology Center, NSTDA, Pathum Thani, Thailand.

PMID: 38063158
DOI: 10.1080/07391102.2023.2291178

Abstract

Tuberculosis (TB), the second leading infectious killer, causes serious public health problems worldwide. To develop novel anti-TB agents, many biochemical studies have targeted the subunit B of DNA gyrase (GyrB), which captures a second DNA segment and responses for ATP hydrolysis. Here, we investigated specific interactions between GyrB residues and existing pyrrolamide derivatives at an electronic level using ab initio fragment molecular orbital (FMO) calculations and designed potent inhibitors against GyrB. The evaluated binding affinities between GyrB and pyrrolamides were confirmed to be consistent with the IC₅₀ values obtained from previous experiments. Thus, we employed the most potent pyrrolamide (compound 1) as a lead compound and proposed novel pyrrolamide derivatives. The specific interactions between GyrB and these derivatives were investigated using molecular mechanic optimizations and FMO calculations. The results revealed that our proposed derivatives had strong hydrogen bonds with Asp79 and Arg141 and exhibited electrostatic interactions with Glu56 and Ile84 of GyrB. In addition, the binding affinity between GyrB and compound 1 was enhanced significantly by the replacement at the R3 site of compound 1. The present results may provide structural concepts for the rational design of potent GyrB inhibitors as anti-TB agents.Communicated by Ramaswamy H. Sarma.

Keywords: DNA gyrase; GyrB; M. tuberculosis; fragment molecular orbital; in silico drug design; inhibitor; molecular dynamics; molecular mechanics; pyrrolamides; specific interactions.