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.

典范的瞬态受体电位通道5（TRPC5）在中枢神经系统，心血管系统，肾脏疾病，癌症的调节中起着关键作用，并且还可能参与肝功能，关节炎，糖尿病相关并发症等。但是，关于TRPC5在细胞或机体水平上起作用的证据很少。仍然需要鉴定新颖且有效的TRPC5通道调节剂以研究TRPC5功能。在这项研究中，基于通过同源性建模获得的hTRPC5结构和预测的结合位点，我们从specs数据库（http://www.specs.net）中对212,736种化合物进行了虚拟筛选，以发现潜在的hTRPC5调节剂。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）过滤器用于筛选大型数据库。此外，使用多软件组合对接，聚类分析和交互分析来选择20个具有新颖骨架的潜在活跃候选对象。在明显的水条件下，对40ns全原子分子动力学（MD）模拟，选择了与hTRPC5具有明显结合亲和力的4个匹配项。MD模拟结果表明4 Hits结合诱导轻微的结构变化并稳定hTRPC5结构。此外，分解自由能证明残基TRP434，LEU437，MET438，ALA441，ILE484，ILE487，LEU488，LEU491，LEU515，ILE517，LEU518，LEU521，PHE531，THR607，VAL610，ILE611，VAL615发挥了关键作用。作为hTRPC5的潜在调节剂，有4首