Discovery of new druggable sites in the anti-cholesterol target HMG-CoA reductase by computational alanine scanning mutagenesis
| Autor: | Diana S. Gesto, Nuno M. F. S. A. Cerqueira, Pedro A. Fernandes, Maria J. Ramos |
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| Rok vydání: | 2013 |
| Předmět: |
Models
Molecular Stereochemistry Dimer Druggability Molecular Conformation Reductase Molecular Dynamics Simulation Catalysis Inorganic Chemistry chemistry.chemical_compound Catalytic Domain Physical and Theoretical Chemistry Alanine Binding Sites biology Chemistry Organic Chemistry Active site Alanine scanning Small molecule Computer Science Applications Molecular Docking Simulation Computational Theory and Mathematics Biochemistry Mutagenesis biology.protein Hydroxymethylglutaryl CoA Reductases Hydroxymethylglutaryl-CoA Reductase Inhibitors Protein Multimerization Homotetramer Protein Binding |
| Zdroj: | Journal of molecular modeling. 20(4) |
| ISSN: | 0948-5023 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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