Pharmacophore modeling and virtual screening studies to design potential COMT inhibitors as new leads
Pharmacophore modeling and virtual screening studies to design potential COMT inhibitors as new leads
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DOI：
10.1016/j.jmgm.2012.10.010
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发表时间：
2013-02-01
影响因子：
2.9
通讯作者：
Latha, N.
中科院分区：
文献类型：
--
作者：
Jatana, Nidhi;Sharma, Aditya;Latha, N.
儿茶酚-O-甲基转移酶(COMT)催化儿茶酚胺的甲基化，包括多巴胺、肾上腺素和去甲肾上腺素等神经递质，导致它们的降解。COMT因其在帕金森氏病(PD)、精神分裂症和抑郁症等多种神经疾病中的作用而成为研究对象。COMT基因与多种等位基因变异相关，其中Val108Met多态是最具临床意义的等位基因。人可溶性COMT的108V型和108M型晶体结构的可用性使我们能够使用基于结构的虚拟筛选方法，通过从锌数据库中筛选中枢神经系统通透性化合物的文库来获得新的命中率。在这项研究中，E-药效团也被用来建立基于一系列已知COMT抑制剂的药效团模型。建立了由一个氢键受体(A)、两个氢键供体(D)和两个芳香环(R)组成的五点药效团模型。然后将这些模型用于筛选锌-CNS渗透性文库，以获得新的命中率。还计算了从两种方法获得的所有命中的物化性质，以获得良好的ADME性质。这些鉴定的HITS可能对进一步的结构优化和生物学评价分析感兴趣。(C)2012 Elsevier Inc.保留所有权利。
Catechol-O-methyltransferase (COMT) catalyzes the methylation of catecholamines, including neuro-transmitters like dopamine, epinephrine and norepinephrine, leading to their degradation. COMT has been a subject of study for its implications in numerous neurological disorders like Parkinson's disease (PD), schizophrenia, and depression. The COMT gene is associated with many allelic variants, the Val108Met polymorphism being the most clinically significant.Availability of crystal structure of both 108V and 108M forms of human soluble-COMT (S-COMT) facilitated us to use structure-based virtual screening approach to obtain new hits by screening a library of CNS permeable compounds from ZINC database. In this study, E-pharmacophore was also used to generate pharmacophore models based on a series of known COMT inhibitors. A five-point pharmacophore model consisting of one hydrogen-bond acceptor (A), two hydrogen bond donors (D), and two aromatic rings (R) was generated for both the polymorphic forms of COMT. These models were then used for filtering ZINC-CNS permeable library to obtain new hits. Physicochemical properties were also calculated for all the hits obtained from both the approaches for favorable ADME properties. These identified hits maybe of interest for further structural optimization and biological evaluation assays. (C) 2012 Elsevier Inc. All rights reserved.