5-羟基Triptamine2A拮抗剂是治疗各种脑血管和心血管疾病的潜在靶标。在这项研究中,我们在与已知拮抗剂的相似性的基础上,开发并进行了筛选ZINC数据库化合物的独特筛选流程,以确定5-羟基Triptamine2A的新型小分子拮抗剂.筛选管道基于2D相似性,3D相异性和2D/3D相似性的组合。入围的化合物被对接到基于5-羟基Triptamine2A同源性的模型,选择具有低结合能的复合物(287个复合物)用于脂质双层中的分子动力学(MD)模拟。与5-羟基Triptamine2A配合物的入围化合物的MD模拟证实了配合物的稳定性,并揭示了新的相互作用见解。受体残基S239、N343、S242、S159、Y370和D155主要参与氢键键合。在F339、F340、F234、W151和W336中观察到π-π堆叠,而在V156、F339、F234、V362、V366、F340、V235、I152和W151中观察到疏水相互作用。我们入围的已知和潜在拮抗剂具有相似的重叠分子相互作用模式。287种潜在的5-羟基雷公藤甲胺2A拮抗剂可以通过实验验证。
5-HydroxyTriptamine 2A antagonists are potential targets for treatment of various cerebrovascular and cardiovascular disorders. In this study, we have developed and performed a unique screening pipeline for filtering ZINC database compounds on the basis of similarities to known antagonists to determine novel small molecule antagonists of 5-HydroxyTriptamine 2A. The screening pipeline is based on 2D similarity, 3D dissimilarity and a combination of 2D/3D similarity. The shortlisted compounds were docked to a 5-HydroxyTriptamine 2A homology-based model, and complexes with low binding energies (287 complexes) were selected for molecular dynamics (MD) simulations in a lipid bilayer. The MD simulations of the shortlisted compounds in complex with 5-HydroxyTriptamine 2A confirmed the stability of the complexes and revealed novel interaction insights. The receptor residues S239, N343, S242, S159, Y370 and D155 predominantly participate in hydrogen bonding. π-π stacking is observed in F339, F340, F234, W151 and W336, whereas hydrophobic interactions are observed amongst V156, F339, F234, V362, V366, F340, V235, I152 and W151. The known and potential antagonists shortlisted by us have similar overlapping molecular interaction patterns. The 287 potential 5-HydroxyTriptamine 2A antagonists may be experimentally verified.