Flavanones: A potential natural inhibitor of the ATP binding site of PknG of <i>Mycobacterium tuberculosis</i>

Over the years, <i>Mycobacterium tuberculosis</i> has been one of the major causes of death worldwide. As several clinical isolates of the bacteria have developed drug resistance against the target sites of the current therapeutic agents, the development of a novel drug is the pressing priority. According to recent studies on <i>Mycobacterium tuberculosis</i>, ATP binding sites of <i>Mycobacterium tuberculosis</i> serine/threonine protein kinases (MTPKs) have been identified as the new promising drug target. Among the several other protein kinases (PKs), Protein kinase G (PknG) was selected for the study because of its crucial role in modulating bacterium’s metabolism to survive in host macrophages. In this work, we have focused on the H37Rv strain of <i>Mycobacterium tuberculosis.</i> A list of 477 flavanones obtained from the PubChem database was docked one by one against the crystallized and refined structure of PknG by <i>in-silico</i> techniques. Initially, potential inhibitors were narrowed down by preliminary docking. Flavanones were then selected using binding energies ranging from −7.9 kcal.mol⁻¹ to −10.8 kcal.mol^−1. This was followed by drug-likeness prediction, redocking analysis, and molecular dynamics simulations. Here, we have used experimentally confirmed drug AX20017 as a reference to determine candidate compounds that can act as potential inhibitors for PknG. PubChem165506, PubChem242065, PubChem688859, PubChem101367767, PubChem3534982, and PubChem42607933 were identified as possible target site inhibitors for PknG with a desirable negative binding energy of −8.1, −8.3, −8.4, −8.8, −8.6 and −7.9 kcal.mol⁻¹ respectively. Communicated by Ramaswamy H. Sarma

多年来，结核分枝杆菌（Mycobacterium tuberculosis）一直是全球主要致死病因之一。随着该细菌的多株临床分离株对当前治疗药物的作用靶点产生耐药性，开发新型抗菌药物已成为当务之急。针对结核分枝杆菌的近期研究表明，该菌丝氨酸/苏氨酸蛋白激酶（Mycobacterium tuberculosis serine/threonine protein kinases, MTPKs）的ATP结合位点已被确定为极具潜力的新型药物靶点。在众多其他蛋白激酶（protein kinases, PKs）中，本研究选取了蛋白激酶G（Protein kinase G, PknG），因其在调控该细菌代谢以在宿主巨噬细胞内存活方面发挥关键作用。本研究聚焦于结核分枝杆菌H37Rv菌株，从PubChem数据库中获取了477种黄烷酮类化合物，通过虚拟（in silico）技术将其逐一与经结晶与纯化的PknG蛋白三维结构进行分子对接。首先通过初步分子对接初步缩小潜在抑制剂的筛选范围，随后选取结合能介于-7.9 kcal·mol⁻¹至-10.8 kcal·mol⁻¹之间的黄烷酮类化合物。后续依次进行了药物相似性预测、重对接分析以及分子动力学模拟。本研究以经实验验证的药物AX20017作为参照，用以筛选可作为PknG潜在抑制剂的候选化合物。最终鉴定出PubChem165506、PubChem242065、PubChem688859、PubChem101367767、PubChem3534982及PubChem42607933这6种化合物可作为PknG的潜在靶点抑制剂，其结合能分别为-8.1、-8.3、-8.4、-8.8、-8.6及-7.9 kcal·mol⁻¹。本文由Ramaswamy H. Sarma转交。

搜集汇总

背景与挑战

背景概述

该数据集总结了针对结核分枝杆菌PknG蛋白ATP结合位点的黄烷酮类化合物筛选研究。研究通过计算机模拟技术对477种黄烷酮进行分子对接分析，筛选出6种具有负结合能的候选化合物作为潜在抑制剂。数据集聚焦于药物发现过程，涉及分子对接、药物相似性预测和分子动力学模拟等方法，旨在为开发新型抗结核药物提供基础。