title: Quantifying intrinsic specificity: a potential complement to affinity in drug screening.
abstract: We report here the investigation of a novel description of specificity in protein-ligand binding based on energy landscape theory. We define a new term, intrinsic specificity ratio (ISR), which describes the level of discrimination in binding free energies of the native basin for a protein-ligand complex from the weaker binding states of the same ligand. We discuss the relationship between the intrinsic specificity we defined here and the conventional definition of specificity. In a docking study of molecules with the enzyme COX-2, we demonstrate a statistical correspondence between ISR value and geometrical shapes of the small molecules binding to COX-2. We further observe that the known selective (nonselective) inhibitors of COX-2 have higher (lower) ISR values. We suggest that intrinsic specificity ratio may be a useful new criterion and a complement to affinity in drug screening and in searching for potential drug lead compounds.
authors.affiliation: State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences Changchun, Jilin, PR China. jin.wang.1@stonybrook.edu
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.forename: Xiliang
authors.initials: X
authors.lastname: Zheng
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Yang
authors.forename: Dale
authors.initials: D
authors.lastname: Drueckhammer
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.forename: Gennardy
authors.initials: G
authors.lastname: Verkhivker
authors.forename: Erkang
authors.initials: E
authors.lastname: Wang
mesh_terms: D051546:Cyclooxygenase 2 / Q000737:chemistry* / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D007700:Kinetics; D008024:Ligands; D013379:Substrate Specificity; D013816:Thermodynamics
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D008024:Ligands; D051546:Cyclooxygenase 2