Lead compounds and key residues of ribosomal protein S1 in drug-resistant Mycobacterium tuberculosis

Yunbao Zhi; Yazhuang Dai; Juanjuan Yang; Shuhua Tan; Donghai Lin; Kejiang Lin

doi:10.1016/j.bioorg.2018.09.024

Lead compounds and key residues of ribosomal protein S1 in drug-resistant Mycobacterium tuberculosis

Bioorg Chem. 2019 Feb:82:58-67. doi: 10.1016/j.bioorg.2018.09.024. Epub 2018 Sep 21.

Authors

Yunbao Zhi¹, Yazhuang Dai², Juanjuan Yang³, Shuhua Tan⁴, Donghai Lin⁵, Kejiang Lin⁶

Affiliations

¹ China Pharmaceutical University, Nanjing 210009, China; Shandong New Time Pharmaceutical Company, Lunan Pharmaceutical Group, Linyi 273400, China.
² China Pharmaceutical University, Nanjing 210009, China; Hangzhou Ipharmacare Information Technology Co., Ltd, Hangzhou 310000, China.
³ College of Biological Science and Biotechnology, Fuzhou University, Fuzhou 350000, China.
⁴ China Pharmaceutical University, Nanjing 210009, China.
⁵ Xiamen University, Xiamen 361102, China.
⁶ China Pharmaceutical University, Nanjing 210009, China. Electronic address: link@cpu.edu.cn.

PMID: 30268974
DOI: 10.1016/j.bioorg.2018.09.024

Abstract

Ribosomal protein S1 (RpsA) has been identified as a novel target of pyrazinoic acid (POA), which is the active form of pyrazinamide (PZA), in vivo. RpsA plays a crucial role in trans-translation, which is widespread in microbes. In our investigation, we first described the discovery of promising RpsA antagonists for drug-resistant mycobacterium (MtRpsAd438A) and M. smegmatis, as well as wild-type M. tuberculosis. These antagonists were discovered via structure/ligand-based virtual screening approaches. A total of 21 targeted compounds were selected by virtual screening, combined scores, affinity, similarities and rules for potential as drugs. Next, the affinities of these compounds for three targeted proteins were tested in vitro by applying various technologies, including fluorescence quenching titration (FQT), saturation transfer difference (STD), and chemical shift perturbation (CSP) assays. The results showed that seven compounds had a high affinity for the targeted proteins. Our discovery set the stage for discovering new chemical entities (NCEs) for PZA-resistant tuberculosis and providing key residues for rational drug design to target RpsA.

Keywords: Drug-resistant; RPS1; Trans-translation; Virtual screening.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antitubercular Agents / chemistry
Antitubercular Agents / pharmacology*
Azoles / chemistry
Azoles / pharmacology*
Bacterial Proteins / antagonists & inhibitors*
Bacterial Proteins / chemistry
Bacterial Proteins / genetics
Binding Sites
Drug Evaluation, Preclinical
Heterocyclic Compounds, 2-Ring / chemistry
Heterocyclic Compounds, 2-Ring / pharmacology*
Microbial Sensitivity Tests
Molecular Docking Simulation
Molecular Dynamics Simulation
Mutation
Mycobacterium smegmatis / drug effects
Mycobacterium tuberculosis / drug effects
Ribosomal Proteins / antagonists & inhibitors*
Ribosomal Proteins / chemistry
Ribosomal Proteins / genetics
Software

Substances

Antitubercular Agents
Azoles
Bacterial Proteins
Heterocyclic Compounds, 2-Ring
Ribosomal Proteins
ribosomal protein S1