Cholesterol is a substance of paramount importance for all animals. However, its high
level in the human body is linked to the two major diseases that kill the world: ischemic
heart disease and stroke. One of the synthetic drugs used in the treatment of
hypercholesterolemia are statins, inhibitors of 3-hydroxy-3-methylglutaryl Cozyme A
reductase (HMGR), which act primarily on the liver by inhibiting a conversion of the
HMG-CoA substrate into mevalonic acid, which is the metabolite Cholesterol
precursor. Studies Molecular Dynamics (MD) combined with Principal Component
Analysis (PCA) were performed to verify the mechanism of the changes in the Cterminal Flap domain form (residues His861, Leu862, Val863, Lys864, Ser865 and
Hys866) after binding substrate and efficient statins in inhibiting the HMGR enzyme. A
total of 500 ns of MD simulation time were performed in this study. Binding Free
Energies calculations were used, which estimate that the structural mechanism of the
Flap is related to an action of the HMGR protein, since domain control or access to the
active site of the enzyme. The results also show that the structural modification of Flap
increases the energy contribution of the system by involving larger interactions with
catalytic residues and, consequently, an ability to inhibit cholesterol production, as
observed for the catalytic His866, which has a very favorable contribution when the
Flap is in the closed state, with energy of -14,802 Kcal/mol, and when the Flap passes
to the open state the contribution is less favorable, with -1,022 Kcal/mol, for 1 inhibitor,
showing that in the closed state the catalytic residue is directly involved and contributes
in a favorable way to the system, leading to a better understanding of the
conformational changes of HMGR after a binding of statin derivatives and HMG-CoA
substrate.
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