高通量虚拟筛选CDK2/Cyclin A2靶点抑制剂

CDK2/Cyclin A2复合蛋白的异常表达与乳腺癌、 口腔癌、 食管鳞状细胞癌的发生密切相关. CDK2/ Cyclin A2复合蛋白的活性位点不同于CDK2单体. 至今临床上尚无靶向此复合蛋白的药物分子. 针对CDK2/Cyclin A2复合蛋白, 以实验报道的10个抑制剂分子构建药效团模型, 通过药物体外药代动力学（ADME）、 Docking、 聚类分析、 毒性预测, 从DrugBank, ChEMBL和TCM@Taiwan 3个数据库约90万组数据中进行高通量虚拟筛选, 进一步进行MD模拟、 MM/PBSA结合自由能计算、 能量分解和平均非共价作用(aNCI)分析, 筛选出3个抑制效果优于阳性实验药Roscovitine的先导分子: DrugBank-2004, DrugBank-583和ChEMBL-7122. 与CDK2蛋白相比, CDK2/Cyclin A2复合蛋白结合位点空间变大, 先导分子与Lys33, Asp86, Lys129和Asp145残基之间的排斥作用有所降低, 导致结合自由能更大.

High-throughput Virtual Screening of CDK2/Cyclin A2 Target Inhibitors

Abnormal expression of CDK2/Cyclin A2 protein is closely related to the occurrence of breast cancer， oral cancer， and esophageal squamous cell carcinoma. The binding pocket of CDK2/Cyclin A2 complex protein is different from that of CDK2 monomer. So far， no inhibitor that targeting CDK2/Cyclin A2 protein has been approved clinically. In order to obtain the high-efficiency inhibitor towards CDK2/Cyclin A2， the high-throughput virtual screening was performed among approximately 900000 molecules based on the three databases including DrugBank， ChEMBL and TCM@Taiwan. The 10 inhibitor molecules reported experimentally were used for pharmacophore models， to screen for hit molecules in above databases by means of docking， ADME， clustering analysis， toxicity prediction. Furthermore， 3 lead molecules including DrugBank-2004， DrugBank-583 and ChEMBL-7122 were screened out after moleculor dynamics（MD） simulation， bin- ding free energy calculation and average non-covalent interaction（aNCI） analysis， which are superior to Roscovitine because of the stronger electrostatic interaction. Moreover， as the result of the larger binding pocket than CDK2， the moderation of repulsion between lead molecules and target residues of Lys33， Asp86， Lys129 and Asp145 is achieved， and thus leading to greater binding free energies. The present work will provide a theoretical basis for the experimental research in the future.