Chemoinformatic identification of novel inhibitors against Mycobacterium tuberculosis L-aspartate α-decarboxylase.
Chemoinformatic identification of novel inhibitors against Mycobacterium tuberculosis L-aspartate α-decarboxylase.
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DOI：
10.1371/journal.pone.0033521
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Swaminathan K
中科院分区：
文献类型：
--
作者：
Sharma R;Kothapalli R;Van Dongen AM;Swaminathan K
L-天冬氨酸α-脱羧酶（ADC）是一类天冬酰依赖性酶，在泛酸途径中催化天冬氨酸转化为β-丙氨酸，这对包括结核分枝杆菌（Mtb）在内的多种微生物的生长至关重要。它只存在于微生物、真菌和植物中，而在动物，特别是人类中不存在，这使它成为一个有前途的药物靶点。我们遵循化学信息学为基础的方法，以确定潜在的药物样抑制剂结核分枝杆菌L-天冬氨酸α-脱羧酶（MtbADC）。Glide项目的基于结构的高通量虚拟筛选（HTVS）模式用于筛选Maybridge、国家癌症研究所（NCI）和美国食品药品监督管理局（FDA）批准的药物数据库中的333，761个分子。如果配体与S-腺苷甲硫氨酸（SAM）脱羧酶（一种人腺苷酰依赖性酶）发生交叉反应，则将其拒绝。根据Lipinski的五项法则和ADMET（吸收、分布、代谢、排泄和毒性）特性，进一步分析了铅分子的理化和药代动力学参数。该分析产生了八种小的潜在药物样抑制剂，其与结晶ADC：富马酸盐和ADC：异天冬酰胺复合物结构的结合位姿一致，并且其骨架支架似乎适合于针对结核病的治疗开发中的进一步实验研究。
L-Aspartate α-decarboxylase (ADC) belongs to a class of pyruvoyl dependent enzymes and catalyzes the conversion of aspartate to β-alanine in the pantothenate pathway, which is critical for the growth of several micro-organisms, including Mycobacterium tuberculosis (Mtb). Its presence only in micro-organisms, fungi and plants and its absence in animals, particularly human, make it a promising drug target. We have followed a chemoinformatics-based approach to identify potential drug-like inhibitors against Mycobacterium tuberculosis L-aspartate α-decarboxylase (MtbADC). The structure-based high throughput virtual screening (HTVS) mode of the Glide program was used to screen 333,761 molecules of the Maybridge, National Cancer Institute (NCI) and Food and Drug Administration (FDA) approved drugs databases. Ligands were rejected if they cross-reacted with S-adenosylmethionine (SAM) decarboxylase, a human pyruvoyl dependent enzyme. The lead molecules were further analyzed for physicochemical and pharmacokinetic parameters, based on Lipinski's rule of five, and ADMET (absorption, distribution, metabolism, excretion and toxicity) properties. This analysis resulted in eight small potential drug-like inhibitors that are in agreement with the binding poses of the crystallographic ADC:fumarate and ADC:isoasparagine complex structures and whose backbone scaffolds seem to be suitable for further experimental studies in therapeutic development against tuberculosis.
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影响因子：
2.9
作者：
Gopalan, Gayathri;Chopra, Sidharth;Swaminathan, Kunchithapadam
通讯作者：
Swaminathan, Kunchithapadam
DOI：
10.1093/jac/dkr472
发表时间：
2012-02
期刊：
The Journal of antimicrobial chemotherapy
影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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