Use of MP2, DFT and semi-emperical calculations of protein-ligand interaction energies and ab initio QSAR in the development of novel statin drugs

Abstract

Previous work (J. Phys. Chem. B, 113, 14810, 2009) has 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 of HMG-CoA reductase, blocking the biosynthesis of cholesterol early in the synthesis pathway. In this work, novel molecular fragments that bind strongly to all areas of the active site have been developed using ab initio correlated methods and attached to known statin drugs to create novel drug candidates that interact more strongly with the enzyme than the original drugs. Interaction energies between small molecule ligands and the target enzyme active site are calculated with all-electron correlated methods such as MP2 and DFT, as well as semi-empirical methods. Various molecular properties of known statin drugs were also correlated to the values of the in vivo potencies (the pIC50) of each drug in order to derive quantitative structure/activity trends. Based on the above work a second generation of drug candidates has been designed to be more specific for the total HMG-CoA reductase active site. Further, Tyr479 has been found to be present in an allosteric binding site, which upon analysis, appears to be a promising site for uncompetitive inhibition of HMG-CoA. The calculations show that the novel drugs candidates developed in this work will be effective inhibitors of both the active and the allosteric site.