title: A novel method to simulate the hydrophobic effect and its application to the ranking of host/guest complexes.
abstract: Solvent entropy change is a major factor in driving the association of hydrophobic species in aqueous solutions. We have developed a novel methodology which simulates the solvation of hydrophobic surfaces by water. A system of virtual solvent particles surrounding the solute governed by arbitrarily determined rules provides a means to estimate the degree of order (Q) imposed by such solvation. Computed changes in Q (dQ) upon complex formation have been found to correlate well with observed binding affinities of host-guest complexes in aqueous solutions. Examples are described which illustrate the ability of dQ calculations to identify the correct ligand pose from a set of decoy complexes as well as provide rank ordering of a set of highly diverse ligand-protein complexes. Comparisons to surface-area-based calculations are discussed. The Q methodology holds great promise in the development of predictive structure-based approaches to drug design, as it provides a relatively simple means to estimate the hydrophobic effect.
authors.affiliation: Computer-Assisted Drug Design, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, New Jersey 08543, USA. arthur.doweyko@bms.com
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Doweyko
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Johnson
mesh_terms: D000465:Algorithms; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003198:Computer Simulation; D015195:Drug Design; D019277:Entropy; D006801:Humans; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D047495:PPAR gamma / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D012997:Solvents; D013816:Thermodynamics
chemical_list: D008024:Ligands; D047495:PPAR gamma; D012997:Solvents