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.

Figure 1

Illustration of the concept of specificity in ligand binding and relationship between intrinsic specificity and the conventional specificity as well as the corresponding energy spectrum: (a) Different receptors binding to the same ligand; (b) Different binding states (modes) of a particular ligand to its receptor; (c) Different ligands binding to the same receptor.

Figure 2

The spectrum and the associated distribution of binding energies for resulting high, medium, and low ISR values of three different ligands binding to Cox-2, respectively, and the binding energy funnel for each. Notice that the sparse part of the spectrum implies there are fewer states, and dense part of the spectrum represented by lines implies there are more states. High ISR has a discrimination between the native and non-native basins. For theoretical details, see Ref. 7. The illustrations of the bottom three funnels are from Ref. 27.

Figure 3

Plot of ISR versus geometrical shapes of the small molecules ranging from linear, to $V$, and to $Y$ binding to COX-2.

Figure 4

Contour map of binding affinity and ISR for 1000 small molecules binding with COX-2, including some known COX-2 selective drugs (red dots), classical nonselective NSAIDs (white and violet), and three drugs with serious side effects ( gray).