Supplementing the Pbsa Approach with Quantum Mechanics to Study the Binding Between CDK2 and N2-Substituted O6-Cyclohexylmethoxyguanine Inhibitors

Because classical Poisson–Boltzman Surface Area (PBSA) model does not allow re-polarization of charges and does not account for charge transfer when a ligand binds to a protein, we have examined a hybrid approach in which we describe the protein–ligand interface by quantum mechanics and the rest of the system with the classical PBSA model. We found this approach to rank order the binding of five N 2 -substituted O 6 -cyclohexylmethoxyguanine inhibitors to CDK2 (cyclin-dependent kinase 2) properly. The calculated binding free energy correlated well with experimental Log(IC 50 ) with a correlation coefficient of 0.94. A regression fit between experimental Log(IC 50 ) and calculated binding free energy yielded a root-mean-square error of 0.48 when Log(IC50) spanned a range over three units. In addition, we observed charge transfer between the ligand and the protein at the interface — an effect not accounted for by the classical PBSA model. We also found that the direct interactions between the protein and the ligands provided the dominant factor to distinguish the binding affinity of the five ligands studied here. This hybrid approach can better prioritize derivatives of lead compounds for synthesis and biological evaluation.