MP2, density functional theory, and semi-empirical calculations of the interaction energies between a series of statin-drug-like molecules and the HMG-CoA reductase active site

In previous work [E.A. Kee, M.C. Livengood, E.E. Carter, M.L. McKenna, M. Cafiero, J. Phys. Chem. B 113 (2009) 14810] it has been shown that the residue Tyr479 in the active site of 3-hydroxy-3-methyglutaryl-coenzyme A (HMG-CoA) reductase exerts a strong attraction on ligands. Statin drugs moderate blood cholesterol levels by acting as competitive inhibitors for this enzyme, blocking the biosynthesis of cholesterol early in the synthesis pathway. In this work a novel molecular fragment that binds strongly to Tyr479 has been developed using ab initio correlated methods and attached to known statin drugs (which bind well to other important residues in the active site) to create novel drug candidates that interact more strongly with the entire enzyme active site than the original drugs. Interaction energies between small molecule ligands and the target enzyme active site are calculated with all-electron density functional theory and semi-empirical methods, showing that the novel drug molecules will likely bind strongly in the active site. Solvation energies are also calculated to confirm behavior of the novel drug candidate molecules in vivo.