The technology advances in combinatorial synthesis of peptide [8] as well as virtual screening of small molecule databases provide a new route [9, 10] to address the above mentioned issue.

Instead of studying a specific pair of biomolecular binding, for example, a receptor-ligand (or receptor-small molecule) complex, one can now search through the sequence space of li-gands or different small molecules and perform the binding experiments for each specific sequence of ligand binding to a particular receptor.

Therefore by exploring the sequences of ligands (typically 106 ~ 109 sequences, a large number which is perfect for the statistical description) or small molecule databases (the number of small molecules can be on the order of 1060), one can explore the biological specificity and function by mimicking the natural evolution selection process with the fittest surviving from the ensemble of ligands.

Initially a diverse set of 720 small molecules were selected from the NCI-Diversity database [49] having molecular weights similar to that of the reference compound SC-558, for which the crystal structure of the COX-2 complex is available (PDB code ICXZ) [50, 51].

From this data, the statistical distribution of the affinity (defined as the free energy difference between the native state and the average of the free energy) of 720 small molecules with COX-2 was described.

In Fig 6, we show the logarithm of the equilibrium constant distribution for the 720 small molecule binding with Cox2.

Although the free energy is in general a complicated function of interactions and entropy, combinatorial library of ligands and database of small molecules provide us a great opportunity to study the interactions and underlying principles of binding.

Different ligands or small molecules will have different specificity for binding with a specific receptor.

Furthermore, the advances of combinatorial chemistry With the capability of generating large number of small molecules at once and high throughput screening provide us a great opportunity of obtaining the statistical information on thermodynamics and kinetics for molecular recognition through the eXploration of the ensemble of sequence space of small molecules (combinatorial ligand binding).

The increase of compound phenotypic screenings over the last years has dramatically increased the number of small molecules with non-annotated protein targets [40—42].

Other methods use local structural comparisons of small molecule binding sites to infer the localization and specificity of binding pockets [25,26] as well as to infer new ligand interactions in known binding pockets [27].

Here, we describe the method alongside the predictions for all the small molecule drugs present in DrugBank [32] against the human 3D proteome.

Briefly, the RFC classifier predicts whether two small molecules are likely to bind the same target-binding site by comparing their structural and chemical properties.

Since structurally similar binding sites are more likely to bind the same small molecule .

Although small changes in the catalytic site could have a dramatic impact on the bind-ing-affinity of a small molecule , the overall high similarity among the Sorafenib predicted binding sites shows a clear trend towards binding site conservation within this set of proteins.

concentrations of the GR agonist Dex including EtOH in the presence of different concentrations of APILUC reporter plus one of three added cofactors: the plasmid for TIF2 or two small molecules (NU6027 and phenanthroline) recently identified in a high throughput screen as accelerators of GR transactivation [30].

4 and 5 show that the dose-response parameters are also well fit by linear-fractional functions for the small molecules NU6027 and phenanthroline [30].

Using the extensively characterized system of GR repression of APl induction in UZOS.rGR cells with a transiently transfected synthetic reporter [8,15,28,29] , we show that four factors (the reporter gene, TIF2, and two small molecules [30]) have the same kinetically-defined mechanism and position of action as in GR-regulated gene induction.