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

Abstract

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.

Statin use in primary inflammatory breast cancer: a cohort study

“…In our study, simvastatin, a highly lipophilic statin, demonstrated less protective effects than atorvastatin, a lesser lipophilic statin. Pharmacologically speaking, atorvastatin is much more potent than simvastatin, with stronger binding capacity to HMG-CoA inhibitors (da Costa et al , 2012), which may explain the better outcomes in our H-statin group, in which the majority of patients were using atorvastatin.…”

Crude Ethanol Extract of Pithecellobium ellipticum as a Potential Lipid‐Lowering Treatment for Hypercholesterolaemia

“…The conformational flexibility has sterically hindered the substrate from binding with the enzyme. Concurrently, the statin structure extends into the narrow pantothenic acid-binding pocket moiety of coenzyme A which eventually blocks the coenzyme A of the substrate [11, 12]. This is why statins are capable of competing with the substrate.…”

A quantum biochemistry investigation of willardiine partial agonism in AMPA receptors

“…10,35 Experimental, computational and crystallographic analysis has been used to describe partial agonism by 5-substituted willardiines in AMPA receptors. The analysis of crystallographic structures can be done based on important methods, such as virtual screening of the distances and sizes of connections, the de novo design, molecular docking and molecular dynamics, 37,38 which are limited by the lack of information on the interaction between specific residues of the receptor and the different ligands, which would be quite useful for the design of new drugs. The analysis of crystallographic structures can be done based on important methods, such as virtual screening of the distances and sizes of connections, the de novo design, molecular docking and molecular dynamics, 37,38 which are limited by the lack of information on the interaction between specific residues of the receptor and the different ligands, which would be quite useful for the design of new drugs.…”