Protein-Small Ligand Interactions
Docking small molecules to a protein is a fundamental step in structure-based drug design. The main approaches are (A) Docking of potential ligands from a compound database, and (B) mapping the protein for the binding sites of molecular probes - small molecules and functional groups - and using the favorable positions for the construction of larger ligands. We develop and apply algorithms for both approaches.
Our basic methodology of docking is very similar to the one we have used for protein-protein docking, and consists of the following steps: (1): Rigid body search to generate a large number of conformations with good shape complementarity, and possibly favorable electrostatics and desolvation, (2) refinement, rescoring and possibly filtering using a more accurate free energy function, (3) clustering of the retained structures, and ranking the clusters on the basis of the average free energy. This algorithm has been implemented for the mapping of proteins using organic solvents as probes, and is being extended to more mainstream docking applications.