From Binding Pockets To Ligand Structure

ANGELINA, EMILIO ; FORLI, STEFANO ; OLSON, ARTHUR

Santiago

Congreso; 10th Congress of the World Association of Theoretical and Computational Chemists (WATOC 2014); 2014

Pontificia Universidad Católica de Chile

The molecular recognition properties of a binding pocket are determined by the amino acids forming the cavity. The spatial arrangements of these amino acids and their physicochemical properties define the shape and the properties that a ligand has to complement in order to be qualified to bind to the pocket.Autoligand (AL) is a grid-based method to predict ligand-binding sites in proteins of known structure. In this work we exploit the AL description of the HIV protease exo-site, a potential allosteric site on the surface of the protease that has been recently discovered, to design novel, fragments-like binders for this protein site. HIV-1 protease (HIV-PR) is a retroviral aspartyl protease (retropepsin) that is essential for the life-cycle of HIV, the retrovirus that causes AIDS. Since all the FDA approved PR inhibitors binds to the active site of the enzyme, resistance to one of them often results in cross-resistance to the others.Therefore, to overcome resistance, drugs with novel mechanisms of action are required. Non-active site, allosteric inhibitors, in combination with active site inhibitors, would likely increase the number of PR mutations required for significant clinical resistance to the highly active anti-retroviral therapy (HAART) cocktails.A previous fragment screen utilizing X-ray crystallography identified a novel binding site on the surface of HIV-PR, termed the "exo-site". One of the 384 fragments screened, 4d9 (2-methylcyclohexanol), bound in this site of the PR in its inhibited, closed form (PDB code: 3kf0). The issue that we want to address in this work is whether the exo-site can accommodate larger (lead-like) fragments capable of inhibiting the protease when combined with active site inhibitors