Computational identification of potential dipeptidyl peptidase (DPP)-IV inhibitors: Structure based virtual screening, molecular dynamics simulation and knowledge based SAR studies

化学 广告 磷酸西他列汀 虚拟筛选 生物信息学 二肽基肽酶-4 计算生物学 分子动力学 药理学 药物发现 生物化学 糖尿病 2型糖尿病 2型糖尿病 计算化学 医学 内分泌学 体外 基因 生物
作者
Virendra Nath,Manish Ramchandani,Neeraj Kumar,Renu Agrawal,Vipin Kumar
出处
期刊:Journal of Molecular Structure [Elsevier BV]
卷期号:1224: 129006-129006 被引量:9
标识
DOI:10.1016/j.molstruc.2020.129006
摘要

Type 2 Diabetes mellitus (T2DM) is a globally leading metabolic problem with increased morbidity and mortality. Current medication therapies in the market to control diabetes are not sufficient and therefore, there is further need to develop more selective and effective treatment approaches. Inhibition of Dipeptidyl-peptidase-IV (DPP-IV) enzyme may serve as an interesting target for developing novel anti-diabetic drug candidate. In the present study, hierarchical virtual screening of drug like compounds was done followed by molecular dynamics simulation and knowledge-based structure-activity relation (SAR) study in order to retrieve hit compound as prospective inhibitors of DPP-IV enzyme. Important amino acid residues present in the active target site were acknowledged as vital and were also found to have similar interactions with the potential hits. Further, in silico technique was undertaken to identify ubiquitous promising hits against DPP-IV enzyme and this was followed by calculation of binding energy and absorption, distribution, metabolism, excretion (ADME) prediction that could possibly support their pharmacokinetic prospective. Furthermore, stability study using molecular dynamics simulation of protein complex was accomplished with the most capable targeted hit established in the present study. In the end, comparative analysis of 3-dimensional binding pose, orientation and planar structure of the potential retrieved hit was done with marketed drugs (alogliptin and sitagliptin) in order to develop knowledge-based structure-activity relationship, which proved the successful designing of DPP-IV enzyme inhibitors.
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