Kristam Rajendra, Rao Shashidhar N, D'Cruz Anne Sudha, Mahadevan Vijayalakshmi, Viswanadhan Vellarkad N
Department of Computational Chemistry, Jubilant Biosys Ltd. #96, Industrial Suburb, 2nd Stage, Yeshwanthpur, Bangalore 560 064, India; School of Chemical & Biotechnology, Shanmugha Arts, Science, Technology, and Research Academy (SASTRA University), Thanjavur, Tamil Nadu 613 402, India.
Tripos International, A Certara Company, St. Louis, MO 63101, USA.
J Mol Graph Model. 2017 Mar;72:112-128. doi: 10.1016/j.jmgm.2017.01.010. Epub 2017 Jan 7.
Transient Receptor Potential Vanilloid, member 1 (TRPV1), is a non-selective cation channel belonging to the transient receptor potential (TRP) family of ion channels. It occurs in the peripheral and central nervous system, activated by a variety of exogenous and endogenous stimuli, thus playing a key role in transmission of pain. This has been a target for chronic pain since more than a decade and a number of antagonists that progressed into clinical trials have failed due to the unexpected side effect of core body temperature rise, thus halting progress in this field. Of late, there has been an upsurge in research on this target, with the rat TRPV1 structure being determined, many new antagonists discovered that are temperature-neutral and many new therapeutic avenues being discovered for TRPV1, including diseases of respiratory and digestive systems, skin and bladder. Towards identifying diverse compounds to decipher the role of this target in various indications, here we report a 3D-QSAR model built using the new topomer-CoMFA methodology on a series of piperazinyl-aryl TRPV1 antagonists and the use of this model, along with a pharmacophore model and the shape of one of the potent compounds of this series, to virtually screen a subset of the ZINC database to find novel and diverse hits. These can serve as starting points to develop modality-selective antagonists for chronic pain and to elucidate the critical role of TRPV1 in the various new therapeutic areas.
瞬时受体电位香草酸亚型1（TRPV1）是一种非选择性阳离子通道，属于离子通道的瞬时受体电位（TRP）家族。它存在于外周和中枢神经系统中，可被多种外源性和内源性刺激激活，因此在疼痛传递中起关键作用。十多年来，它一直是慢性疼痛的治疗靶点，许多进入临床试验的拮抗剂由于出现核心体温升高这一意外副作用而失败，从而阻碍了该领域的进展。最近，对这个靶点的研究热潮涌起，大鼠TRPV1的结构已被确定，发现了许多对温度不敏感的新型拮抗剂，还发现了TRPV1的许多新治疗途径，包括呼吸系统、消化系统、皮肤和膀胱疾病。为了鉴定各种化合物以阐明该靶点在各种适应症中的作用，在此我们报告了一种使用新的topomer-CoMFA方法构建的3D-QSAR模型，该模型基于一系列哌嗪基-芳基TRPV1拮抗剂，以及该模型的使用，连同药效团模型和该系列中一种强效化合物的形状，对ZINC数据库的一个子集进行虚拟筛选，以找到新颖多样的命中化合物。这些可作为开发针对慢性疼痛的模式选择性拮抗剂以及阐明TRPV1在各种新治疗领域中关键作用的起点。
