title: Calculation of cyclodextrin binding affinities: energy, entropy, and implications for drug design.
abstract: The second generation Mining Minima method yields binding affinities accurate to within 0.8 kcal/mol for the associations of alpha-, beta-, and gamma-cyclodextrin with benzene, resorcinol, flurbiprofen, naproxen, and nabumetone. These calculations require hours to a day on a commodity computer. The calculations also indicate that the changes in configurational entropy upon binding oppose association by as much as 24 kcal/mol and result primarily from a narrowing of energy wells in the bound versus the free state, rather than from a drop in the number of distinct low-energy conformations on binding. Also, the configurational entropy is found to vary substantially among the bound conformations of a given cyclodextrin-guest complex. This result suggests that the configurational entropy must be accounted for to reliably rank docked conformations in both host-guest and ligand-protein complexes. In close analogy with the common experimental observation of entropy-enthalpy compensation, the computed entropy changes show a near-linear relationship with the changes in mean potential plus solvation energy.
authors.affiliation: Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, Rockville, Maryland 20850, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Chia-En
authors.initials: CE
authors.lastname: Chang
authors.forename: Michael K
authors.initials: MK
authors.lastname: Gilson
mesh_terms: D000465:Algorithms; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry*; D001554:Benzene / Q000737:chemistry; D001665:Binding Sites; D002074:Butanones / Q000737:chemistry; D003198:Computer Simulation; D003505:Cyclodextrins / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods*; D015195:Drug Design; D004735:Energy Transfer; D019277:Entropy; D005480:Flurbiprofen / Q000737:chemistry; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D000077430:Nabumetone; D009288:Naproxen / Q000737:chemistry; D012118:Resorcinols / Q000737:chemistry
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002074:Butanones; D003505:Cyclodextrins; D012118:Resorcinols; D009288:Naproxen; D005480:Flurbiprofen; D001554:Benzene; D000077430:Nabumetone; C031389:resorcinol