Dynamic ligand design and combinatorial optimization: Designing inhibitorsto endothiapepsin

The dynamic ligand design (DLD) algorithm, an automated method for the crea tion of novel ligands, links up small functional groups that have been plac ed in energetically favorable positions in the binding site of a target mol ecule. The positions and orientations of the small functional groups can be determined using the multicopy simultaneous search approach (MCSS) or expe rimental data. In this work the original DLD methodology is extended by usi ng a modified version of the pseudo-potential energy function. A novel simu lated annealing protocol is presented for optimizing the pseudo-potential e nergy of ligands in the binding site; the protocol is expected to be applic able to other optimization problems. The utility of the method is illustrat ed by designing an inhibitor for endothiapepsin, The binding affinity of th e inhibitor is assessed using a thermodynamic cycle that decomposes the bin ding free energy into a sum of translational, rotational, configurational, hydrophobic, and electrostatic contributions. The calculations suggest that the designed molecule will bind endothiapepsin with high affinity. (C) 200 0 Wiley-Liss, Inc.