Hossain Mohammad Uzzal, Oany Arafat Rahman, Ahmad Shah Adil Ishtiyaq, Hasan Md Anayet, Khan Md Arif, Siddikey Md Al Ahad
Department of Biotechnology and Genetic Engineering, Faculty of Life Scisence, Mawlana Bhashani Science and Technology University, Santosh, Tangail, Bangladesh.
Department of Genetic Engineering and Biotechnology, Faculty of Biological Sciences, University of Chittagong, Chittagong 4331, Bangladesh.
Comput Biol Chem. 2016 Dec;65:29-36. doi: 10.1016/j.compbiolchem.2016.10.002. Epub 2016 Oct 7.
Chagas is a parasitic disease with major threat to public health due to its resistance against commonly available drugs. Trypanothione reductase (TryR) is the key enzyme to develop this disease. Though this enzyme is well thought-out as potential drug target, the accurate structure of enzyme-inhibitor complex is required to design a potential inhibitor which is less available for TryR. In this research, we aimed to investigate the advanced drug over the available existing drugs by designing inhibitors as well as to identify a new enzyme-inhibitor complex that may act as a template for drug design. A set of analogues were designed from a known inhibitor Quinacrine Mustard (QUM) to identify the effective inhibitor against this enzyme. Further, the pharmacoinformatics elucidation and structural properties of designed inhibitor proposed effective drug candidates against Chagas disease. Molecular docking study suggests that a designed inhibitor has higher binding affinity in both crystal and modeled TryR and also poses similar interacting residues as of crystal TryR-QUM complex structure. The comparative studies based on in silico prediction proposed an enzyme-inhibitor complex which could be effective to control the disease activity. So our in silico analysis based on TryR built model, Pharmacophore and docking analysis might play an important role for the development of novel therapy for Chagas disease. But both animal model experiments and clinical trials must be done to confirm the efficacy of the therapy.
恰加斯病是一种对公共卫生构成重大威胁的寄生虫病，因为它对常用药物具有抗性。锥虫硫醇还原酶（TryR）是引发这种疾病的关键酶。尽管这种酶被公认为潜在的药物靶点，但需要酶 - 抑制剂复合物的精确结构来设计对TryR不太容易获得的潜在抑制剂。在这项研究中，我们旨在通过设计抑制剂来研究比现有药物更先进的药物，并鉴定一种可能作为药物设计模板的新的酶 - 抑制剂复合物。从已知抑制剂喹吖因芥（QUM）设计了一组类似物，以鉴定针对该酶的有效抑制剂。此外，所设计抑制剂的药物信息学阐释和结构特性提出了针对恰加斯病的有效候选药物。分子对接研究表明，一种设计的抑制剂在晶体和建模的TryR中都具有更高的结合亲和力，并且与晶体TryR - QUM复合物结构具有相似的相互作用残基。基于计算机模拟预测的比较研究提出了一种酶 - 抑制剂复合物，它可能对控制疾病活性有效。因此，我们基于TryR构建模型、药效团和对接分析的计算机模拟分析可能对恰加斯病新疗法的开发发挥重要作用。但必须进行动物模型实验和临床试验以确认该疗法的疗效。
