title: Inhibitor docking screened by the modified SAFE_p scoring function: application to cyclic urea HIV-1 PR inhibitors.
abstract: Our laboratory has in the past developed a method for the prediction of ligand binding free energies to proteins, referred to as SAFE_p (Solvent free energy predictor). Previously, we have applied this protocol for the prediction of the binding free energy of peptidic and cyclic urea HIV-1 PR inhibitors, whose X-ray structures bound to enzyme are known. In this work, we present the first account of a docking simulation, where the ligand conformations were screened and inhibitor ranking was predicted on the basis of a modified SAFE_p approach, for a set of cyclic urea-HIV-1 PR complexes whose structures are not known. We show that the optimal dielectric constant for docking is rather high, in line with the values needed to reproduce some protein residue properties, like pKa's. Our protocol is able to reproduce most of the observed binding ranking, even in the case that the components of the equation are not fitted to experimental data. Partition of the binding free energy into pocket and residue contributions sheds light into the importance of the inhibitor's fragments and on the prediction of "hot spots" for resistance mutations.
authors: Departamento de Química Orgánica, Universidad de Santiago de Compostela, 15782-Santiago de Compostela, Spain.
authors: Santiago
authors: S
authors: Vilar
authors: M Carmen
authors: MC
authors: Villaverde
authors: Fredy
authors: F
authors: Sussman
mesh_terms: D000465:Algorithms; D000596:Amino Acids / Q000737:chemistry; D001381:Azepines / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D003198:Computer Simulation; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D055672:Static Electricity; D013816:Thermodynamics; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism
chemical_list: D000596:Amino Acids; D001381:Azepines; D017320:HIV Protease Inhibitors; C112386:SD 146 cyclic urea; C112387:XK 216; C104713:XK 263; C112388:XV 638; D014508:Urea; D016333:HIV Protease; C085816:DMP 323; C099851:DMP 450