title: Prediction and analysis of binding affinities for chemically diverse HIV-1 PR inhibitors by the modified SAFE_p approach.
abstract: One of the biggest challenges in the "in silico" screening of enzyme ligands is to have a protocol that could predict the ligand binding free energies. In our group we have developed a very simple screening function (referred to as solvent accessibility free energy of binding predictor, SAFE_p) which we have applied previously to the study of peptidic HIV-1 protease (HIV-1 PR) inhibitors and later to cyclic urea type HIV-1 PR inhibitors. In this work, we have extended the SAFE_p protocol to a chemically diverse set of HIV-1 PR inhibitors with binding constants that differ by several orders of magnitude. The resulting function is able to reproduce the ranking and in many cases the value of the inhibitor binding affinities for the HIV-1 PR, with accuracy comparable with that of costlier protocols. We also demonstrate that the binding pocket SAFE_p analysis can contribute to the understanding of the physical forces that participate in ligand binding. The analysis tools afforded by our protocol have allowed us to identify an induced fit phenomena mediated by the inhibitor and have demonstrated that larger fragments do not necessarily contribute the most to the binding free energy, an outcome partially brought about by the substantial role the desolvation penalty plays in the energetics of binding. Finally, we have revisited the effect of the Asp dyad protonation state on the predicted binding affinities.
authors.affiliation: Departamento de Química Orgánica, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Arenas
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Villaverde
authors.forename: Fredy
authors.initials: F
authors.lastname: Sussman
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D008024:Ligands; D015394:Molecular Structure; D012997:Solvents / Q000737:chemistry; D013816:Thermodynamics
chemical_list: D017320:HIV Protease Inhibitors; D008024:Ligands; D012997:Solvents