Statin Inhibition of HMG-CoA Reductase by Quantum Biochemistry Computations

Hundreds of millions of adults have high cholesterol, which has generated a billionaire market of drugs. Patents covering the leading statins have expired recently, pressuring the development of new drugs. Statins act by inhibiting the HMG-CoA reductase in the process of converting HMG-CoA to mevalonate, a committed step in the biosynthesis of cholesterol. It is observed in clinical trials that this action decreases by 20 to 60% the low density protein (LDL) cholesterol levels, reducing coronary events by up to one-third over a five years period. In this work, considering the crystallographic data of HMGR complexed with statins, we perform a computer simulation within an ab-initio quantum mechanical approach, based on the density functional theory, to investigate the details of the binding interaction energies of the statins atorvastatin, rosuvastatin, fluvastatin, and simvastatin to the HMGR enzyme. Our purpose is to elucidate why statins have differences in their efficiency to reduce cholesterol levels, by obtaining and comparing the interaction energy between the HMGR residues and the ligand atoms. The main advantage of our methodology is the possibility to evaluate what amino acid residues contribute more intensely to the stabilization of the statin-HMGR complex, a very helpful information for drug design.