基于吡咯烷与正丁烷类衍生物CCR5拮抗剂的药效团模型构建

吡咯烷与正丁烷类CCR5(化学趋化因子受体5)拮抗剂可通过抑制人类免疫缺陷病毒(HIV-1)包膜蛋白与CCR5的相互作用而阻断病毒进入细胞. 本文使用已知拮抗剂结构和活性信息构建了一个三维药效团模型. 按照Catalyst/HypoGen模块的要求, 选择了25个结构和活性均具备差异性的分子作为药效团产生的训练集. 其中训练集分子以IC50值表示的生物活性值跨度为0.06到10000 nmol·L-1. 最好的药效团模型(Hypo 1)由两个正离子化特征以及三个疏水特征组成, 训练集预测相关系数为0.924, 均方根偏差为1.068. 模型用于预测由74个分子组成的测试集化合物活性, 结果表明模型可以提供较好的活性预测结果并用于新的拮抗剂的设计.

Pharmacophore Model Generation Based on Pyrrolidine-and Butane-derived CCR5 Antagonists

A three-dimensional pharmacophore model was developed for a considerable number of pyrrolidinebased and butane-based chemokine (C-C motif) receptor 5(CCR5) antagonists, which can block the entry of human immunodeficiency virus type 1 (HIV-1) by inhibiting the interaction of HIV-1 envelope protein and CCR5. The pharmacophore model was generated using a training set consisting of 25 carefully selected antagonists with the diverse molecular architecture and bioactivity, as required by the Catalyst/HypoGen program. The activity of the training set molecules expressed in IC50 (half-inhibitory concentration) covered from 0.06 to 10000 nmol· L-1.The most predictive pharmacophore model (Hypo 1), consisting of two positive ionizable points and three hydrophobic groups, had a correlation of 0.924 and a root mean square of 1.068, and a cost difference of 63.67 bits between the null cost and the total cost. The model was applied in predicting the activity of 74 compounds as a test set. The results indicated that the model was able to provide clear guidelines and accurate activity prediction for novel antagonist design.