The statins are inhibitors of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase (HMG-CoAR), and are utilized to decrease levels of atherogenic lipoproteins in patients with, or who are at high risk of, cardiovascular disease. This study describes the inhibition of a recombinant, catalytic fragment of human HMG-CoAR by a new statin, rosuvastatin (CRESTOR®). Binding is reversible and involves an initial complex [inhibition constant involving the enzyme–inhibitor complex (E.I), Ki, ≈1 nM], which undergoes a slow transition (t1/2 to reach steady state is 33–360 s) to give tighter association [steady-state inhibition constant involving E.I and the second E.I complex in a two-step mechanism (E.I*), Ki*, ≈0.1 nM]. At steady state, rosuvastatin is at least as potent as atorvastatin, cerivastatin and simvastatin. It is more potent than fluvastatin and pravastatin. For rosuvastatin, inhibition kinetics are competitive with respect to HMG-CoA and non-competitive when NADPH is varied. At 37°C, binding is linked to a large favourable enthalpy change [ ΔH° =−69.0 kJ/mol (−16.5 kcal/mol)] and a small entropic penalty [T ΔS°=−9.6 kJ/mol (−2.3 kcal/mol)]. These characteristics, and the high affinity relative to that of 3S-HMG-CoA (Kd≈6.6 μM), are discussed in relation to the crystal structures of complexes with HMG-CoAR.

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