Department of Chemistry, Quantum Theory Project, University of Florida, Gainesville, FL 32611-7200, USA.
J Mol Graph Model. 2013 Sep;45:84-97. doi: 10.1016/j.jmgm.2013.08.009. Epub 2013 Aug 16.
Chagas' is a fatal disease that affects millions of people worldwide. The lack of safe and effective treatments for Chagas' highlights the need for the discovery of new drugs to fight the disease. Trypanosoma cruzi, the parasitic cause of Chagas' disease, synthesizes a trans-sialidase (TcTS) enzyme responsible for the transfer of sialic acids from the host cell surface to glycoconjugates on the parasitic cell surface. TcTS has no human analogs and is vital to the life cycle of T. cruzi, making TcTS an important enzyme for drug design against Chagas' disease. We use fragment docking to generate various e-pharmacophore hypotheses depicting protein residues important for ligand binding. Virtual screening of the ZINC Clean Leads database with more than 4 million compounds using the e-pharmacophore models found 82 potential inhibitors of TcTS. Molecular dynamics and free energy of binding calculations were used to rank the compounds based on their affinity for TcTS. Two compounds-ZINC13359679 and ZINC02576132-were found to be the most promising lead candidates for TcTS inhibition, and their binding modes are analyzed in detail.
克氏锥虫病是一种致命疾病，影响着全球数百万人。缺乏安全有效的克氏锥虫病治疗方法突显了发现新药物来对抗这种疾病的必要性。克氏锥虫病的寄生虫病因 Trypanosoma cruzi 合成了一种转涎酸酶（TcTS），负责将唾液酸从宿主细胞表面转移到寄生虫细胞表面的糖缀合物上。TcTS 没有人类类似物，对 T. cruzi 的生命周期至关重要，因此 TcTS 是针对克氏锥虫病的药物设计的重要酶。我们使用片段对接来生成各种电子药效团假说，描绘出对配体结合重要的蛋白质残基。使用电子药效团模型对超过 400 万种化合物的 ZINC Clean Leads 数据库进行虚拟筛选，发现了 82 种潜在的 TcTS 抑制剂。分子动力学和结合自由能计算用于根据它们与 TcTS 的亲和力对化合物进行排名。发现两种化合物-ZINC13359679 和 ZINC02576132-是 TcTS 抑制的最有前途的先导候选物，并详细分析了它们的结合模式。
