Yadav Manoj Kumar, Singh Amisha, Swati D
Department of Bioinformatics, MMV, Banaras Hindu University, Varanasi, 221005, India,
Appl Biochem Biotechnol. 2014 Aug;173(8):2174-88. doi: 10.1007/s12010-014-1023-y. Epub 2014 Jun 27.
Malaria is one of the most infectious diseases in the world. Plasmodium vivax, the pathogen causing endemic malaria in humans worldwide, is responsible for extensive disease morbidity. Due to the emergence of resistance to common anti-malarial drugs, there is a continuous need to develop a new class of drugs for this pathogen. P. vivax cysteine protease, also known as vivapain-2, plays an important role in haemoglobin hydrolysis and is considered essential for the survival of the parasite. The three-dimensional (3D) structure of vivapain-2 is not predicted experimentally, so its structure is modelled by using comparative modelling approach and further validated by Qualitative Model Energy Analysis (QMEAN) and RAMPAGE tools. The potential binding site of selected vivapain-2 structure has been detected by grid-based function prediction method. Drug targets and their respective drugs similar to vivapain-2 have been identified using three publicly available databases: STITCH 3.1, DrugBank and Therapeutic Target Database (TTD). The second approach of this work focuses on docking study of selected drug E-64 against vivapain-2 protein. Docking reveals crucial information about key residues (Asn281, Cys283, Val396 and Asp398) that are responsible for holding the ligand in the active site. The similarity-search criterion is used for the preparation of our in-house database of drugs, obtained from filtering the drugs from the DrugBank database. A five-point 3D pharmacophore model is generated for the docked complex of vivapain-2 with E-64. This study of 3D pharmacophore-based virtual screening results in identifying three new drugs, amongst which one is approved and the other two are experimentally proved. The ADMET properties of these drugs are found to be in the desired range. These drugs with novel scaffolds may act as potent drugs for treating malaria caused by P. vivax.
疟疾是世界上传染性最强的疾病之一。间日疟原虫是全球人类地方性疟疾的病原体，会导致大量发病。由于对常见抗疟药物产生了耐药性，因此持续需要为这种病原体开发新型药物。间日疟原虫半胱氨酸蛋白酶，也称为间日疟蛋白酶-2，在血红蛋白水解中起重要作用，被认为是该寄生虫生存所必需的。间日疟蛋白酶-2的三维（3D）结构尚未通过实验预测，因此通过比较建模方法对其结构进行建模，并通过定性模型能量分析（QMEAN）和RAMPAGE工具进一步验证。通过基于网格的功能预测方法检测了所选间日疟蛋白酶-2结构的潜在结合位点。使用三个公开可用的数据库：STITCH 3.1、DrugBank和治疗靶点数据库（TTD），确定了与间日疟蛋白酶-2相似的药物靶点及其各自的药物。这项工作的第二种方法侧重于所选药物E-64与间日疟蛋白酶-2蛋白的对接研究。对接揭示了负责将配体保持在活性位点的关键残基（Asn281、Cys283、Val396和Asp398）的关键信息。相似性搜索标准用于制备我们从DrugBank数据库中筛选药物得到的内部药物数据库。为间日疟蛋白酶-2与E-64的对接复合物生成了一个五点3D药效团模型。这项基于3D药效团的虚拟筛选研究确定了三种新药，其中一种已获批准，另外两种已通过实验证明。发现这些药物的ADMET特性在所需范围内。这些具有新型支架的药物可能成为治疗间日疟原虫引起的疟疾的有效药物。
