title: Ligand conformational and solvation/desolvation free energy in protein-ligand complex formation.
abstract: In this study, an extensive sampling of the conformational space of nine HIV-1 protease inhibitors was performed to estimate the uncertainty with which a single-conformation scoring scheme approximates the ligand-protein binding free energy. The SMD implicit solvation/desolvation energy and gas-phase PM6-DH2 energy were calculated for a set of 1600 conformations of each ligand. The probability density functions of the energies were compared with the values obtained from the single-conformation approach and from a short ab initio molecular dynamics simulation. The relative uncertainty in the score within the set of nine inhibitors was calculated to be 3.5 kcal·mol(-1) and 2.7 kcal·mol(-1) for the single-conformation and short dynamics, respectively. These results, though limited to the consideration of flexible ligands, provide a valuable insight into the precision of rigid models in the current computer-aided drug design.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Kolár
authors.forename: Jindrich
authors.initials: J
authors.lastname: Fanfrlík
authors.forename: Pavel
authors.initials: P
authors.lastname: Hobza
mesh_terms: D017076:Computer-Aided Design; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011480:Protease Inhibitors / Q000737:chemistry; D011789:Quantum Theory; D012997:Solvents / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D008024:Ligands; D011480:Protease Inhibitors; D012997:Solvents; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1