Grupo GEPAMOL, Centro de Investigaciones Biomédicas, Universidad del Quindío, Armenia, Colombia.
SCIProt, Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes, CONICET, Roque Sáenz Peña 352, Bernal, Argentina.
BMC Genomics. 2018 Nov 29;19(1):856. doi: 10.1186/s12864-018-5223-7.
Thiazolidinone derivatives show inhibitory activity (IC) against the Toxoplasma gondii parasite, as well as high selectivity with high therapeutic index. To disclose the target proteins of the thiazolidinone core in this parasite, we explored in silico the active sites of different T. gondii proteins and estimated the binding-free energy of reported thiazolidinone molecules with inhibitory effect on invasion and replication of the parasite inside host cells. This enabled us to describe some of the most suitable structural characteristics to design a compound derived from the thiazolidinone core.
The best binding affinity was observed in the active site of kinase proteins, we selected the active site of the T. gondii ROP18 kinase, because it is an important factor for the virulence and survival of the parasite. We present the possible effect of a derivative of thiazolidinone core in the active site of T. gondii ROP18 and described some characteristics of substituent groups that could improve the affinity and specificity of compounds derived from the thiazolidinone core against T. gondii.
The results of our study suggest that compounds derived from the thiazolidinone core have a preference for protein kinases of T. gondii, being promising compounds for the development of new drugs with potential anti-toxoplasmosis activity. Our findings highlight the importance of use computational studies for the understanding of the action mechanism of compounds with biological activity.
噻唑烷酮衍生物对刚地弓形虫寄生虫表现出抑制活性（IC），并且具有高选择性和高治疗指数。为了揭示该寄生虫中噻唑烷酮核心的靶蛋白，我们通过计算机探索了不同刚地弓形虫蛋白的活性部位，并估计了具有抑制宿主细胞内寄生虫入侵和复制作用的报告噻唑烷酮分子的结合自由能。这使我们能够描述一些最适合的结构特征，以设计源自噻唑烷酮核心的化合物。
在激酶蛋白的活性部位观察到最佳结合亲和力，我们选择了刚地弓形虫 ROP18 激酶的活性部位，因为它是寄生虫毒力和生存的重要因素。我们提出了噻唑烷酮核心衍生物在刚地弓形虫 ROP18 活性部位的可能作用，并描述了一些取代基的特征，这些取代基可以提高源自噻唑烷酮核心的化合物对刚地弓形虫的亲和力和特异性。
我们的研究结果表明，源自噻唑烷酮核心的化合物对刚地弓形虫的蛋白激酶具有偏好性，是开发具有潜在抗弓形虫活性的新药的有前途的化合物。我们的研究结果强调了使用计算研究来理解具有生物活性的化合物的作用机制的重要性。
