The
enzyme 3-hydroxy-3-methyl-glutaryl-CoA
reductase (
HMG-CoA-R) is the fundamental target for the treatment of
hypercholesterolemia nowadays. The
HMG-CoA-R clinical active site inhibitors (
statins) are among the most widespread and profitable drugs ever sold but their side effects (
myopathies, sometimes severe) still limit their use, which makes the finding of alternatives to
statins a field of intense research. In this line, we address here a new strategy for inhibiting the homotetrameric
HMG-CoA-R. The
enzyme consists of a "dimer of dimers", each dimer having two active sites. We pursue here the inhibition of
enzyme oligomerization, through
drug binding to the dimer interface. We have computationally mutated 232 interfacial residues by
alanine and calculated the loss in binding free energy among the monomers that build up each dimer of the homotetramer. This led to the identification of the (ten) key residues for the formation of the active dimer (Glu528, Ile531, Met534, Tyr644, Glu665, Asn686, Lys692, Lys735, Met742, and Val863). The results show that these residues are located in two specific spots of the
protein with a cleft shape, whose shape and size is favorable for small
drug binding. It is expectable that small molecules specifically bound to these druggable pockets will have a major effect on the oligomerization of the
protein or/and in active site formation. This paves the way for the discovery of new families of inhibitors of
HMG-CoA-R.