a Department of Pharmacoinformatics , National Institute of Pharmaceutical Education and Research (NIPER) , Sector-67, S. A. S. Nagar 160 062 , Punjab , India.
b Department of Medicinal Chemistry , National Institute of Pharmaceutical Education and Research (NIPER) , Sector-67, S. A. S. Nagar 160 062 , Punjab , India.
J Biomol Struct Dyn. 2016;34(1):1-14. doi: 10.1080/07391102.2015.1005137. Epub 2015 Feb 11.
Aspartate-semialdehyde dehydrogenase (ASADH; EC 1.2.1.11) is a key enzyme in the biosynthesis of essential amino acids in prokaryotes and fungi, inhibition of ASADH leads to the development of novel antitubercular agents. In the present work, a combined structure and ligand-based pharmacophore modeling, molecular docking, and molecular dynamics (MD) approaches were employed to identify potent inhibitors of mycobacterium tuberculosis (Mtb)-ASADH. The structure-based pharmacophore hypothesis consists of three hydrogen bond acceptor (HBA), two negatively ionizable, and one positively ionizable center, while ligand-based pharmacophore consists of additional one HBA and one hydrogen bond donor features. The validated pharmacophore models were used to screen the chemical databases (ZINC and NCI). The screened hits were subjected to ADME and toxicity filters, and subsequently to the molecular docking analysis. Best-docked 25 compounds carry the characteristics of highly electronegative functional groups (-COOH and -NO2) on both sides and exhibited the H-bonding interactions with highly conserved residues Arg99, Arg249, and His256. For further validation of docking results, MD simulation studies were carried out on two representative compounds NSC51108 and ZINC04203124. Both the compounds remain bound to the key active residues of Mtb-ASADH during the MD simulations. These identified hits can be further used for lead optimization and in the design more potent inhibitors against Mtb-ASADH.
天冬氨酸半醛脱氢酶（ASADH；EC 1.2.1.11）是原核生物和真菌中必需氨基酸生物合成的关键酶，ASADH 的抑制作用导致了新型抗结核药物的发展。在本工作中，采用了组合的结构和基于配体的药效团模型、分子对接和分子动力学（MD）方法，以鉴定结核分枝杆菌（Mtb）-ASADH 的有效抑制剂。基于结构的药效团假设由三个氢键受体（HBA）、两个可离子化和一个可离子化中心组成，而基于配体的药效团由另外一个 HBA 和一个氢键供体特征组成。验证后的药效团模型被用于筛选化学数据库（ZINC 和 NCI）。筛选出的命中物经过 ADME 和毒性过滤，然后进行分子对接分析。最佳对接的 25 种化合物在两侧都具有高度电负性的官能团（-COOH 和-NO2），并与高度保守的残基 Arg99、Arg249 和 His256 发生氢键相互作用。为了进一步验证对接结果，对两种代表性化合物 NSC51108 和 ZINC04203124 进行了 MD 模拟研究。在 MD 模拟过程中，这两种化合物都保持与 Mtb-ASADH 的关键活性残基结合。这些鉴定出的命中物可以进一步用于先导化合物优化和设计更有效的 Mtb-ASADH 抑制剂。
