Explaining statin inhibition effectiveness of HMG-CoA reductase by quantum biochemistry computations

By taking advantage of the crystallographic data of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) complexed with statins, a quantum biochemistry study based on the density functional theory is performed to estimate the interaction energy for each statin when one considers binding pockets of different sizes. Assuming a correlation between statin potency and the strength of the total HMGR-statin binding energy, clinical data as well as IC(50) values of these cholesterol-lowering drugs are successfully explained only after stabilization of the calculated total binding energy for a larger size of the ligand-interacting HGMR region, one with a radius of at least 12.0 Å. Actually, the binding pocket radius suggested by classic works, which was based solely on the interpretation of crystallographic data of the HMGR-statin complex, is smaller than that necessary to achieve total binding energy convergence in our simulations. Atorvastatin and rosuvastatin are shown to be the most strongly bound HMGR inhibitors, while simvastatin and fluvastatin are the weakest ones. A binding site, interaction energy between residues and statin atoms, and residues domain (BIRD) panel is constructed, indicating clear quantum biochemistry-based routes for the development of new statin derivatives.