Quantifying intrinsic specificity: a potential complement to affinity in drug screening.
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.
Wang
Jin
J
State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences Changchun, Jilin, PR China. jin.wang.1@stonybrook.edu
Zheng
Xiliang
X
Yang
Yongliang
Y
Drueckhammer
Dale
D
Yang
Wei
W
Verkhivker
Gennardy
G
Wang
Erkang
E
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
D052246:Cyclooxygenase 2 Inhibitors; D008024:Ligands; D051546:Cyclooxygenase 2