Abstract

Tuberculosis is one of the leading causes of death across the world. The treatment regimens for tuberculosis are well established, but still the control of the disease faces many challenges such as lengthy treatment protocols, drug resistance and toxicity. In the present work, mycolic acid methyl transferase (MmaA1), a protein involved in the maturation of mycolic acids in the biochemical pathway of the Mycobacterium, was studied for novel drug discovery. The homology model of the MmaA1 protein was built and validated by using computational techniques. The MmaA1 protein has 286 amino acid residues consisting of 10 α-helices and 7 β-sheets. The active site of the MmaA1 protein was identified using CASTp, SiteMap and PatchDock. Virtual screening studies were performed with two small molecule ligand databases: Asinex synergy and Diverse_Elite_Gold_Platinum databases having a total of 43,446 molecules and generated 1,30,814 conformers against the predicted and validated active site of the MmaA1 protein. Binding analysis showed that the residues ASP 19, PHE 22, TRP 30, TYR 32, TRP 74 and ALA 77 of MmaA1 protein have consistent interactions with the ligands. The hit ligands were further filtered by in silico ADME properties to eliminate potentially toxic molecules. Of the top 10 molecules, 3-(2-morpholinoacetamido)-N-(1,4-dihydro-4-oxoquinazolin-6-yl) benzamide was synthesised and screened for in vitro anti-TB activity against Mtb H37Rv using MABA assay. The compound and its intermediates exhibited good in vitro anti-TB activity which can be taken up for future lead optimisation studies.

Graphical abstract

Structure based virtual screening study was performed using a validated homology model against small molecules from two virtual compound libraries. Synthesised the lead compound 3-(2-morpholinoacetamido)-N-(1,4-dihydro-4-oxoquinazolin-6-yl)benzamide obtained from virtual screening. In vitro activity against Mtb H37Rv has given a promising result.

中文翻译：

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基于结构的药物设计、合成和筛选作为新型抗结核药物的 MmaA1 抑制剂。

摘要

结核病是全世界主要的死亡原因之一。结核病的治疗方案已经确立，但该疾病的控制仍面临许多挑战，例如冗长的治疗方案、耐药性和毒性。在目前的工作中，分枝杆菌酸甲基转移酶 (MmaA1)，一种参与分枝杆菌生化途径中分枝杆菌酸成熟的蛋白质，被研究用于新药发现。MmaA1 蛋白的同源模型是通过使用计算技术建立和验证的。MmaA1 蛋白有 286 个氨基酸残基，由 10 个 α-螺旋和 7 个 β-折叠组成。使用 CASTp、SiteMap 和 PatchDock 鉴定了 MmaA1 蛋白的活性位点。使用两个小分子配体数据库进行虚拟筛选研究：Asinex Synergy 和 Diverse_Elite_Gold_Platinum 数据库，共有 43,446 个分子，并针对预测和验证的 MmaA1 蛋白活性位点生成了 1,30,814 个构象异构体。结合分析表明，MmaA1 蛋白的残基 ASP 19、PHE 22、TRP 30、TYR 32、TRP 74 和 ALA 77 与配体具有一致的相互作用。命中配体通过计算机 ADME 特性进一步过滤，以消除潜在的有毒分子。ñ - （1,4-二氢-4-氧喹唑啉-6-基）苯甲酰胺的合成和体外抗结核病活性筛选针对Mtb的使用MABA测定分枝杆菌H37Rv。该化合物及其中间体表现出良好的体外抗结核活性，可用于未来的先导优化研究。

图形概要

使用针对来自两个虚拟化合物库的小分子的经过验证的同源模型进行基于结构的虚拟筛选研究。合成了虚拟筛选得到的先导化合物3-(2-morpholinoacetamido) -N- (1,4-dihydro-4-oxoquinazolin-6-yl)benzamide。针对 Mtb H37Rv 的体外活性给出了有希望的结果。