Tripathi Sunil K, Soundarya Rajendran Naga, Singh Poonam, Singh Sanjeev K
Computer-Aided Drug Designing and Molecular Modeling Lab, Department of Bioinformatics, Alagappa University, Karaikudi, 630 003, Tamil Nadu, India.
Chem Biol Drug Des. 2015 Feb;85(2):107-18. doi: 10.1111/cbdd.12376. Epub 2014 Jul 12.
The fundamental of molecular modeling is the interaction and binding to form a complex, because it explains the action of most drugs to a receptor active site. In the present study, different semiempirical (RM1, AM1, PM3, MNDO) and ab initio (HF, DFT) charge models were investigated for their performance in prediction of docking pose against CDK2 proteins with their respective inhibitor. Further, multiple docking approaches and Prime/MM-GBSA calculations were applied to predict the binding mode with respective charge model against CDK2 inhibitors. A reliable docking result was obtained using RRD, which showed significance improvement on ligand binding poses and docking score accuracy to the IFD. The combined use of RRD and Prime/MM-GBSA method could give a high correlation between the predicted binding free energy and experimental biological activity. The preliminary results point out that AM1 could be a precious charge model for design of new drugs with enhanced success rate. As a very similar result was also found for a different system of the protein-ligand binding, the suggested scoring function based on AM1 method seems to be applicable in drug design. The results from this study can provide insights into highest success rate for design of potent and selective CDK2 inhibitors.
分子建模的基础是相互作用和结合形成复合物，因为它解释了大多数药物对受体活性位点的作用。在本研究中，研究了不同的半经验（RM1、AM1、PM3、MNDO）和从头算（HF、DFT）电荷模型在预测与CDK2蛋白及其各自抑制剂对接构象时的性能。此外，应用了多种对接方法和Prime/MM-GBSA计算来预测与CDK2抑制剂各自电荷模型的结合模式。使用RRD获得了可靠的对接结果，该结果显示在配体结合构象和对接得分准确性方面相对于IFD有显著提高。RRD和Prime/MM-GBSA方法的联合使用可以在预测的结合自由能和实验生物活性之间产生高度相关性。初步结果表明，AM1可能是一种用于设计成功率更高的新药的宝贵电荷模型。由于在不同的蛋白质-配体结合系统中也发现了非常相似的结果，基于AM1方法的建议评分函数似乎适用于药物设计。本研究的结果可为设计高效、选择性的CDK2抑制剂的最高成功率提供见解。
