Transferable scoring function based on semiempirical quantum mechanical PM6-DH2 method: CDK2 with 15 structurally diverse inhibitors

Abstract

A semiempirical quantum mechanical PM6-DH2 method accurately covering the dispersion interaction and H-bonding was used to score fifteen structurally diverse CDK2 inhibitors. The geometries of all the complexes were taken from the X-ray structures and were reoptimised by the PM6-DH2 method in continuum water. The total scoring function was constructed as an estimate of the binding free energy, i.e., as a sum of the interaction enthalpy, interaction entropy and the corrections for the inhibitor desolvation and deformation energies. The applied scoring function contains a clear thermodynamical terms and does not involve any adjustable empirical parameter. The best correlations with the experimental inhibition constants (ln K (i)) were found for bare interaction enthalpy (r (2) = 0.87) and interaction enthalpy corrected for ligand desolvation and deformation energies (r (2) = 0.77); when the entropic term was considered, however, the correlation becomes worse but still acceptable (r (2) = 0.52). The resulting correlation based on the PM6-DH2 scoring function is better than previously published function based on various docking/scoring, SAR studies or advanced QM/MM approach, however, the robustness is limited by number of available experimental data used in the correlation. Since a very similar correlation between the experimental and theoretical results was found also for a different system of the HIV-1 protease, the suggested scoring function based on the PM6-DH2 method seems to be applicable in drug design, even if diverse protein-ligand complexes have to be ranked.

The Semiempirical Quantum Mechanical Scoring Function for In Silico Drug Design

“…[93] The best correlation with the experimental binding data was obtained when only the DE int and DDG solv terms were considered. CDK2 inhibitors were, however, less flexible and the corrections for the deformation and entropy played less important roles than in the case of HIV PR inhibitors.…”

“…[69,81,[92][93][94] In the first study, a series of HIV PR inhibitors were docked using UCSF DOCK and rescored by the PM6-DH2 scoring function. [69] The QM-based rescoring improved the docking results significantly (Figure 4 A,B).…”

A semiempirical approach to ligand‐binding affinities: Dependence on the Hamiltonian and corrections

“…17,18,19 They also employ the more recent PM6 20 method with corrections for dispersion and hydrogen-bond interactions (DH2). 21,22 They use a single minimised structure of the complex, 3 although they have shown that energies calculated from a minimised structure of the ligand deviates by 13 kJ/mol on average from those calculated on an ensemble of structures from a MD simulation.…”

Open challenges in structure-based virtual screening: Receptor modeling, target flexibility consideration and active site water molecules description

“…Future developments in these areas, coupled with an enhanced description of the physics underlying macromolecular interaction [232,[283][284][285][286][287][288][289][290][291][292][293][294][295][296], will be key for more predictive computational tools in structure-based drug discovery and design. Building the most reliable models is still based, and will probably always be, on the deep knowledge of the system or event under study.…”