title: Free energies of ligand binding for structurally diverse compounds.
abstract: The one-step perturbation approach is an efficient means to calculate many relative free energies from a common reference compound. Combining lessons learned in previous studies, an application of the method is presented that allows for the calculation of relative binding free energies for structurally rather diverse compounds from only a few simulations. Based on the well known statistical-mechanical perturbation formula, the results do not require any empirical parameters, or training sets, only limited knowledge of the binding characteristics of the ligands suffices to design appropriate reference compounds. Depending on the choice of reference compound, relative free energies of binding rigid ligands to the ligand-binding domain of the estrogen receptor can be obtained that show good agreement with the experimental values. The approach presented here can easily be applied to many rigid ligands, and it should be relatively easy to extend the method to account for ligand flexibility. The free-energy calculations can be straightforwardly parallelized, allowing for an efficient means to understand and predict relative binding free energies.
authors.affiliation: Laboratory of Physical Chemistry, Swiss Federal Institute of Technology, Eidgenössische Technische Hochschule-Hönggerberg, CH-8093 Zurich, Switzerland.
authors.forename: Chris
authors.initials: C
authors.lastname: Oostenbrink
authors.forename: Wilfred F
authors.initials: WF
authors.lastname: van Gunsteren
mesh_terms: D000465:Algorithms; D000818:Animals; D001665:Binding Sites; D004958:Estradiol / Q000737:chemistry; D045166:Estradiol Congeners / Q000737:chemistry; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry*; D011960:Receptors, Estrogen / Q000737:chemistry; D012984:Software; D013816:Thermodynamics
chemical_list: D045166:Estradiol Congeners; D008024:Ligands; D011506:Proteins; D011960:Receptors, Estrogen; D004958:Estradiol