| Introduction | 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. |
| Introduction | 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. |
| Introduction | 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. |
| Microscopic Atomic Binding Model and Simulation Results | 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]. |
| Microscopic Atomic Binding Model and Simulation Results | 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. |
| Microscopic Atomic Binding Model and Simulation Results | In Fig 6, we show the logarithm of the equilibrium constant distribution for the 720 small molecule binding with Cox2. |
| Theory and Analytical Models | 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. |
| Theory and Analytical Models | Different ligands or small molecules will have different specificity for binding with a specific receptor. |
| Theory and Analytical Models | 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). |