FLEXIBLE DOCKING AND DESIGN

Docking and design are the major computational steps toward understand ing and affecting receptor-ligand interactions. The flexibility of man y ligands makes these calculations difficult and requires the developm ent and use of special methods. The need for such tools is illustrated by two examples: the design of protease inhibitors and the analysis a nd design of peptide antigens binding to specific MHC receptors. We re view the computational concepts that have been extended from rigid-bod y to flexible docking, as well as the following important strategies f or flexible docking and design: (a) Monte Carlo/molecular dynamics doc king, (b) in-site combinatorial search, (c) ligand build-up, and (d) s ite mapping and fragment assembly. The use of empirical free energy as a target function is discussed. Due to the rapid development of the m ethodology, most new methods have been tested on only a limited number of applications and are likely to improve results obtained by more tr aditional computational or graphic tools.