Liu Bin, Zhang Wei, Guo Sheng, Zuo Zhili
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China.
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, PR China.
J Mol Graph Model. 2021 Jan;102:107795. doi: 10.1016/j.jmgm.2020.107795. Epub 2020 Oct 31.
Canonical transient receptor potential channel 5 (TRPC5) plays a key role in the regulation of central nervous system, cardiovascular system, kidney disease, cancer, and could be also involved in liver function, arthritis, diabetes-associated complications and so on. However, evidence of TRPC5 function on cellular or organismic levels is sparse. There is still a need for identifying novel and efficient TRPC5 channel modulators to study TRPC5 function. In this study, based on the hTRPC5 structure obtained by homology modeling and the predicted binding site, we have performed virtual screening of 212,736 compounds from the specs database（http://www.specs.net) to find potential hTRPC5 modulators. Lipinski and Veber rules, ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) and PAINS (Pan Assay Interference structures) filters were used to screen the large database. Further, multi-software combination docking, cluster analysis and interaction analysis were used to select 20 potential active candidates with novel skeleton. 4 Hits, bearing appreciable binding affinity with hTRPC5 were selected for 40ns all-atom molecular dynamics (MD) simulations under explicit water conditions. The MD simulation results suggested that the 4 Hits binding induces a slight structural change and stabilizes the hTRPC5 structure. In addition, decomposition free energy demonstrated that residues TRP434, LEU437, MET438, ALA441, ILE484, ILE487, LEU488, LEU491, LEU515, ILE517, LEU518, LEU521, PHE531, THR607, VAL610, ILE611, VAL615 played the critical role on system stability. 4 Hits, as potential modulators of hTRPC5, may be potential leads to develop effective therapeutics hTRPC5-associated diseases.
典型瞬时受体电位通道5（TRPC5）在中枢神经系统、心血管系统、肾脏疾病、癌症的调节中起关键作用，还可能参与肝功能、关节炎、糖尿病相关并发症等。然而，TRPC5在细胞或机体水平上功能的证据很少。仍然需要鉴定新型高效的TRPC5通道调节剂来研究TRPC5的功能。在本研究中，基于通过同源建模获得的hTRPC5结构和预测的结合位点，我们对来自specs数据库（http://www.specs.net）的212,736种化合物进行了虚拟筛选，以寻找潜在的hTRPC5调节剂。使用Lipinski和Veber规则、ADMET（吸收、分布、代谢、排泄、毒性）和PAINS（泛分析干扰结构）过滤器对大型数据库进行筛选。此外，采用多软件组合对接、聚类分析和相互作用分析来选择20个具有新型骨架的潜在活性候选物。选择了4个与hTRPC5具有可观结合亲和力的命中物，在明确的水条件下进行40ns全原子分子动力学（MD）模拟。MD模拟结果表明，4个命中物的结合引起轻微的结构变化并稳定了hTRPC5结构。此外，分解自由能表明，残基TRP434、LEU437、MET438、ALA441、ILE484、ILE487、LEU488、LEU491、LEU515、ILE517、LEU518、LEU521、PHE531、THR607、VAL610、ILE611、VAL615对系统稳定性起关键作用。4个命中物作为hTRPC5的潜在调节剂，可能是开发治疗hTRPC5相关疾病有效疗法的潜在先导物。
