Article
Supplementing the Pbsa Approach with Quantum Mechanics to Study the Binding Between CDK2 and N2-Substituted O6-Cyclohexylmethoxyguanine Inhibitors
Journal of Theoretical and Computational Chemistry
(2010)
Abstract
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 N2-substituted O6-cyclohexylmethoxyguanine inhibitors to CDK2 (cyclin-dependent kinase 2) properly. The calculated binding free energy correlated well with experimental Log(IC50) with a correlation coefficient of 0.94. A regression fit between experimental Log(IC50) 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.
Keywords
- PBSA,
- density functional theory,
- quantum mechanics,
- CDK2,
- binding affinity
Disciplines
Publication Date
January 6, 2010
DOI
10.1142/S0219633610005876
Citation Information
Juying Shi, Zhuan Lu, Qianling Zhang, Mingliang Wang, et al.. "Supplementing the Pbsa Approach with Quantum Mechanics to Study the Binding Between CDK2 and N2-Substituted O6-Cyclohexylmethoxyguanine Inhibitors" Journal of Theoretical and Computational Chemistry Vol. 9 Iss. 3 (2010) p. 543 - 559 Available at: http://works.bepress.com/chung-wong/19/