Discovery of acetohydroxyacid synthase inhibitors as anti-tuberculosis lead compounds from natural products

Yanhong Niu; Zhili Wu; Qianfang Hu; Yuchen Wu; Qihua Jiang; Xiaolan Yang

doi:10.1016/j.bmc.2024.118041

Discovery of acetohydroxyacid synthase inhibitors as anti-tuberculosis lead compounds from natural products

Bioorg Med Chem. 2024 Dec 10:118:118041. doi: 10.1016/j.bmc.2024.118041. Online ahead of print.

Authors

Yanhong Niu¹, Zhili Wu¹, Qianfang Hu², Yuchen Wu¹, Qihua Jiang³, Xiaolan Yang⁴

Affiliations

¹ Key Laboratory of Medical Laboratory Diagnostics of the Education Ministry, College of Laboratory Medicine, Chongqing Medical University, No. 1, Yixueyuan Road, Yuzhong Dist, Chongqing 400016, China.
² The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
³ College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.
⁴ Key Laboratory of Medical Laboratory Diagnostics of the Education Ministry, College of Laboratory Medicine, Chongqing Medical University, No. 1, Yixueyuan Road, Yuzhong Dist, Chongqing 400016, China. Electronic address: xiaolanyang666@cqmu.edu.cn.

PMID: 39708691
DOI: 10.1016/j.bmc.2024.118041

Abstract

Acetohydroxy acid synthase (AHAS) is a key enzyme that catalyzes the synthesis of branched-chain amino acids, which is indispensable for the survival and growth of Mycobacterium tuberculosis (Mtb). Aim to discover new AHAS inhibitors from natural products, here we performed computer assistant target-based screening for Mtb-AHAS inhibitors using Discovery Studio on TCMSP and SELLECK libraries. Mtb-AHAS structure was first simulated and verified for docking, and 80 compounds with top LIBDOCK and CDDOCK scores were obtained. By experimental verification, four compounds namely Salvianolic acid A, Embelin, Celastrol and Wushanicaritin showed inhibition potency against Mtb-AHAS with IC50 ranging from 805.5 nM-32.36 μM. The most potential inhibitor Celastrol exhibited bacteriostatic activity for both Mycobacterium smegmatis and Mycobacterium tuberculosis with MIC of 62.5 μM and 80 μM, respectively. This study revealed that Celastrol is the potential Mtb-AHAS inhibitor as an anti-tuberculosis lead compound.

Keywords: Acetohydroxyacid synthase (AHAS); Inhibitors; Mycobacterium tuberculosis; Natural compound; Screening.