天然代谢产物熊果酸作为结核分枝杆菌休眠调节因子DosR的抑制剂：来自分子对接、分子动力学模拟和自由能分析的证据

Natural Metabolite Ursolic Acid as an Inhibitor of Dormancy Regulator DosR of : Evidence from Molecular Docking, Molecular Dynamics Simulation and Free Energy Analysis.

作者信息

Jee Babban, Sharma Prem Prakash, Goel Vijay Kumar, Kumar Sanjay, Singh Yogesh, Rathi Brijesh

机构信息

Department of Health Research, Ministry of Health and Family Welfare, Government of India, New Delhi, 110001, India.

Laboratory for Translational Chemistry and Drug Discovery, Department of Chemistry, Hansraj College, University of Delhi, Delhi, 110007, India.

出版信息

Curr Comput Aided Drug Des. 2023;19(6):425-437. doi: 10.2174/1573409919666230201100543.

DOI:10.2174/1573409919666230201100543

PMID:36722482

Abstract

BACKGROUND

DosR is a transcriptional regulator of Mycobacterium tuberculosis (MTB), governing the expression of a set of nearly 50 genes that is often referred to as 'dormancy regulon'. The inhibition of DosR expression by an appropriate inhibitor may be a crucial step against MTB.

OBJECTIVE

We targeted the DosR with natural metabolites, ursolic acid (UA) and carvacrol (CV), using in silico approaches.

METHODS

The molecular docking, molecular dynamics (MD) simulation for 200 ns, calculation of binding energies by MM-GBSA method, and ADMET calculation were performed to evaluate the inhibitory potential of natural metabolites ursolic acid (UA) and carvacrol (CV) against DosR of MTB.

RESULTS

Our study demonstrated that UA displayed significant compatibility with DosR during the 200 ns timeframe of MD simulation. The thermodynamic binding energies by MM-GBSA also suggested UA conformational stability within the binding pocket. The SwissADME, pkCSM, and OSIRIS DataWarrior showed a drug-likeness profile of UA, where Lipinski profile was satisfied with one violation (MogP > 4.15) with no toxicities, no mutagenicity, no reproductive effect, and no irritant nature.

CONCLUSION

The present study suggests that UA has the potency to inhibit the DosR expression and warrants further investigation on harnessing its clinical potential.

摘要

背景

DosR是结核分枝杆菌（MTB）的一种转录调节因子，调控一组近50个基因的表达，这组基因通常被称为“休眠调节子”。用合适的抑制剂抑制DosR表达可能是对抗MTB的关键步骤。

目的

我们使用计算机模拟方法，以天然代谢产物熊果酸（UA）和香芹酚（CV）靶向DosR。

方法

进行分子对接、200纳秒的分子动力学（MD）模拟、采用MM - GBSA方法计算结合能以及进行ADMET计算，以评估天然代谢产物熊果酸（UA）和香芹酚（CV）对MTB的DosR的抑制潜力。

结果

我们的研究表明，在MD模拟的200纳秒时间范围内，UA与DosR表现出显著的相容性。MM - GBSA计算的热力学结合能也表明UA在结合口袋内的构象稳定性。SwissADME、pkCSM和OSIRIS DataWarrior显示UA具有类药特性，其中Lipinski规则有一项不满足（MogP > 4.15），但无毒性、无致突变性、无生殖影响且无刺激性。