基于Topomer CoMFA技术的AKR1C3选择性抑制剂的研究

Study of AKR1C3 selective inhibitors based on Topomer CoMFA technology

醛酮还原酶(AKR1C3)是治疗去势抵抗性前列腺癌(CRPC)的重要靶点,寻找高选择性的AKR1C3抑制剂是该靶点研究的热点和难点。本文采用Topomer CoMFA技术,对46个AKR1C3选择性抑制剂进行三维定量构效关系研究,得到3D-QSAR模型,其交互验证系数q2为0.59,非交叉相关系数r^(2)为0.918,主成分数N为5,q^(2)_(p red)为0.98,结果表明该模型有较好的预测能力。采用Topomer Search技术在Decoy数据库中进行R基团的筛选,选择RN值最大的10个Ra片段和8个Rb片段进行拼接,获得7个活性预测值高于模板分子,3个活性预测值与模板分子相当的化合物。最后,用分子对接技术研究所设计的新化合物与AKR1C3的作用模式,发现化合物N05和N06可以同时与关键酶催化位点(OS)和选择性口袋SP1中的氨基酸残基Tyr55和Asn167发生作用,说明所设计的AKR1C3抑制剂具有较高的AKR1C3选择性。

Aldoketone reductase(AKR1C3)is an important target for the treatment of castration-resistant prostate cancer(CRPC),and the search for highly selective AKR1C3 inhibitors is a hotspot and difficulty in the research of this target.In this paper,Topomer CoMFA technology was used to study the three-dimensional quantitative structure-activity relationship of 46 AKR1C3 selective inhibitors,and the 3D-QSAR model was obtained.The cross-validation coefficient q2 was 0.59,the non-cross-correlation coefficient r2 was 0.918,the principal component number N was 5 and q^(2)_(p red) was 0.98.These results showed that the model had good predictive ability.Topomer search technology was used to screen R groups in Decoy database,ten Ra fragments and eight Rb fragments were chosen to be splicing,then,seven compounds with predicted activity values higher than the template molecule,and three compounds with predicted activity values equal to the template molecule were obtained.Finally,the molecular docking technology was used to study the interaction between protein AKR1C3 and the new designed compounds.It was found that compounds N05 and N06 had hydrogen bonding with Tyr55 and Asn167 residues in oxyanion site(OS)and high selective pocket SP1,respectively.This result indicated that the designed AKR1C3 inhibitors had high AKR1C3 selectivity.