Venugopal Vandavasi, Datta Alok K, Bhattacharyya Dhananjay, Dasgupta Dipak, Banerjee Rahul
Crystallography and Molecular Biology Division, Saha Institute of Nuclear Physics, Bidhannagar, Kolkata 700 064, India.
Acta Crystallogr D Biol Crystallogr. 2009 Nov;65(Pt 11):1187-95. doi: 10.1107/S0907444909034234. Epub 2009 Oct 22.
Drug development against Leishmania donovani, the pathogen that causes visceral leishmaniasis in humans, is currently an active area of research given the widespread prevalence of the disease and the emergence of resistant strains. The immunosuppressive drug cyclosporin is known to have antiparasitic activity against a variety of pathogens. The receptor for cyclosporin is the protein cyclophilin, which is a ubiquitous peptidylprolyl isomerase. The crystal structure of cyclophilin from L. donovani complexed with cyclosporin has been solved at 2.6 A resolution. The thermodynamic parameters of the interaction have been determined using spectroscopic and calorimetric techniques. A detailed effort has been made to predict the thermodynamic parameters of binding from computations based on the three-dimensional crystal structure. These results were in good agreement with the corresponding experimental values. Furthermore, the structural and biophysical results have been discussed in the context of leishmanial drug resistance and could also set the stage for the design of potent non-immunosuppressive antileishmanials.
鉴于内脏利什曼病的广泛流行以及耐药菌株的出现，针对引起人类内脏利什曼病的病原体——杜氏利什曼原虫的药物研发，目前是一个活跃的研究领域。免疫抑制药物环孢菌素已知对多种病原体具有抗寄生虫活性。环孢菌素的受体是亲环蛋白，它是一种普遍存在的肽基脯氨酰异构酶。已解析出杜氏利什曼原虫亲环蛋白与环孢菌素复合物的晶体结构，分辨率为2.6埃。利用光谱学和量热技术确定了相互作用的热力学参数。基于三维晶体结构，已通过计算详细预测了结合的热力学参数。这些结果与相应的实验值高度吻合。此外，已在利什曼原虫耐药性的背景下讨论了结构和生物物理结果，这也可为设计有效的非免疫抑制性抗利什曼原虫药物奠定基础。
