Discovery of new druggable sites in the anti-cholesterol target HMG-CoA reductase by computational alanine scanning mutagenesis

• Type: Article in International Scientific Journal
• Date: 2014

Authors

Gesto, DS (Author) Other; Cerqueira, NMFSA (Author) Other; Ramos, MJ (Author) FCUP; Fernandes, PA (Author) FCUP

Journal

Title: Journal Of Molecular Modeling

Vol. 20

ISSN: 1610-2940

Publisher: Springer Nature

Indexing

ISI Web of Knowledge - 10 Citations

Scopus - 11 Citations

Scientific classification

FOS: Natural sciences > Chemical sciences

Other information

Authenticus ID: P-009-A3H

DOI: 10.1007/s00894-014-2178-8

Abstract (EN): 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 13