title: Critical evaluation of methods to incorporate entropy loss upon binding in high-throughput docking.
abstract: Proper accounting of the positional/orientational/conformational entropy loss associated with protein-ligand binding is important to obtain reliable predictions of binding affinity. Herein, we critically examine two simplified statistical mechanics-based approaches, namely a constant penalty per rotor method, and a more rigorous method, referred to here as the partition function-based scoring (PFS) method, to account for such entropy losses in high-throughput docking calculations. Our results on the estrogen receptor beta and dihydrofolate reductase proteins demonstrate that, while the constant penalty method over-penalizes molecules for their conformational flexibility, the PFS method behaves in a more "DeltaG-like" manner by penalizing different rotors differently depending on their residual entropy in the bound state. Furthermore, in contrast to no entropic penalty or the constant penalty approximation, the PFS method does not exhibit any bias towards either rigid or flexible molecules in the hit list. Preliminary enrichment studies using a lead-like random molecular database suggest that an accurate representation of the "true" energy landscape of the protein-ligand complex is critical for reliable predictions of relative binding affinities by the PFS method.
authors.affiliation: Structural Biology and Computational Chemistry Department, Chemical and Screening Sciences Division, Wyeth Research, Collegeville, Pennsylvania 19426, USA.
authors.forename: Sumeet
authors.initials: S
authors.lastname: Salaniwal
authors.forename: Eric S
authors.initials: ES
authors.lastname: Manas
authors.forename: Juan C
authors.initials: JC
authors.lastname: Alvarez
authors.forename: Rayomand J
authors.initials: RJ
authors.lastname: Unwalla
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D004054:Diethylstilbestrol / Q000378:metabolism / Q000494:pharmacology; D019277:Entropy; D004965:Estrogen Antagonists / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000737:chemistry / Q000378:metabolism; D005493:Folic Acid Antagonists / Q000378:metabolism / Q000494:pharmacology; D019833:Genistein / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation; D012399:Rotation; D013696:Temperature; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000378:metabolism
chemical_list: D004965:Estrogen Antagonists; D047629:Estrogen Receptor beta; D005493:Folic Acid Antagonists; D008024:Ligands; D004054:Diethylstilbestrol; D019833:Genistein; D013762:Tetrahydrofolate Dehydrogenase