HMG-CoA is reduced by HMG-CoA reductase (HMGR), otherwise known as NADPH. When simvastatin is hydrolyzed in the body into the B-hydroxyacid form, it becomes a potent inhibitor of HMG-CoA reductase.

Simvastatin inhibits HMGR by binding to the substrate binding site. The binding site for the substrate is a pocket like structure called the “cis loop.” When simvastatin binds to this pocket the substrate, HMG-CoA, is sterically blocked from reacting in the site. Also, when simvastatin is bound to HMGR some of the catalytically relevant residues near the carboxyl end of HMGR are disordered. The interactions responsible for keeping the simvastatin attached to the inhibitor are ionic and polar interactions.