Department of Biological Engineering, Inha University, Incheon, Republic of Korea, 402-751.
Clin Proteomics. 2012 Feb 3;9(1):1. doi: 10.1186/1559-0275-9-1.
Aspergillus is a leading causative agent for fungal morbidity and mortality in immuno-compromised patients. To identify a putative target to design or identify new antifungal drug, against Aspergillus is required. In our previous work, we have analyzed the various biochemical pathways, and we found Ketol Acid Reducto-Isomerase (KARI) an enzyme involves in the amino acid biosynthesis, could be a better target. This enzyme was found to be unique by comparing to host proteome through BLASTp analysis. A homology based model of KARI was generated by Swiss model server. The generated model had been validated by PROCHECK and WHAT IF programs. The Zinc library was generated within the limitation of the Lipinski rule of five, for docking study. Based on the dock-score six molecules have been studied for ADME/TOX analysis and subjected for pharmacophore model generation. The Zinc ID of the potential inhibitors is ZINC00720614, ZINC01068126, ZINC0923, ZINC02090678, ZINC00663057 and ZINC02284065 and found to be pharmacologically active agonist and antagonist of KARI. This study is an attempt to Insilco evaluation of the KARI as a drug target and the screened inhibitors could help in the development of the better drug against Aspergillus.
曲霉菌是导致免疫功能低下患者真菌感染发病率和死亡率的主要病原体。为了设计或鉴定针对曲霉菌的新型抗真菌药物，需要确定一个潜在的靶标。在我们之前的工作中，我们分析了各种生化途径，发现参与氨基酸生物合成的酮酸还原异构酶（KARI）可能是一个更好的靶标。通过 BLASTp 分析比较宿主蛋白质组，发现该酶具有独特性。通过 Swiss Model Server 生成了 KARI 的同源模型。通过 PROCHECK 和 WHAT IF 程序对生成的模型进行了验证。在对接研究中，在 Lipinski 五规则的限制内生成了锌库。基于对接评分，对 6 种分子进行了 ADME/TOX 分析，并进行了药效基团模型生成。潜在抑制剂的锌 ID 为 ZINC00720614、ZINC01068126、ZINC0923、ZINC02090678、ZINC00663057 和 ZINC02284065，被发现是 KARI 的药理学活性激动剂和拮抗剂。本研究试图对 KARI 作为药物靶标进行计算机评估，筛选出的抑制剂可能有助于开发针对曲霉菌的更好药物。
