Raza Muslim, Khan Zahid, Ahmad Aftab, Raza Saleem, Khan Ajab, Mohammadzai Imdad Ullah, Zada Shah
Institute of Chemical Sciences, University of Peshawar, Peshawar-25120, Pakistan; State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, China.
Institute of Chemical Sciences, University of Peshawar, Peshawar-25120, Pakistan.
Comput Biol Chem. 2017 Dec;71:10-19. doi: 10.1016/j.compbiolchem.2017.09.002. Epub 2017 Sep 15.
Growing resistance in malarial parasites, particularly in Plasmodium falciparum needs a serious search for the discovery of novel drug targets. Inosine monophosphate dehydrogenase (IMPDH) is an important target for antimalarial drug discovery process in P. falciparum for the treatment of malaria. In the absence of x-ray crystal structure of this enzyme, homology modeling proved to be a reasonable alternate to study substrate binding mechanisms of this enzyme. In this study, a 3-D homology model for P. falciparum IMPDH was constructed taking human IMPDH (PDB code 1NF7) as template. Furthermore, an in-silico combinatorial library of ribavirin (RVP) derivatives (1347 molecules) was designed and virtually screened for ligands having selectively greater binding affinity with Plasmodium falciparum IMPDH relative to human IMPDH II. A total of five Ribavirin derivatives were identified as having greater binding affinity (-126 to -108Kcal/mol and -9.4 to -8.6Kcal/mol) with Plasmodium falciparum IMPDH. These five inhibitors should be used as selective and potent for Plasmodium falciparum IMPDH. Such type of study will provide information to synthetic medicinal chemist to enhance the potential of compounds (RVP derivatives) as chemotherapeutic agents to fight against the increasing burden of malarial infections.
疟原虫，尤其是恶性疟原虫的耐药性不断增强，这需要认真寻找新的药物靶点。肌苷单磷酸脱氢酶（IMPDH）是恶性疟原虫抗疟药物研发过程中的一个重要靶点，用于疟疾治疗。由于缺乏该酶的X射线晶体结构，同源建模被证明是研究该酶底物结合机制的合理替代方法。在本研究中，以人IMPDH（PDB代码1NF7）为模板构建了恶性疟原虫IMPDH的三维同源模型。此外，设计了利巴韦林（RVP）衍生物的虚拟组合文库（1347个分子），并对与恶性疟原虫IMPDH相比与人IMPDH II具有选择性更高结合亲和力的配体进行了虚拟筛选。共鉴定出五种利巴韦林衍生物与恶性疟原虫IMPDH具有更高的结合亲和力（-126至-108千卡/摩尔和-9.4至-8.6千卡/摩尔）。这五种抑制剂应被用作对恶性疟原虫IMPDH具有选择性和强效性的药物。此类研究将为合成药物化学家提供信息，以增强化合物（RVP衍生物）作为抗疟感染日益增加负担的化疗药物的潜力。
