Structure-based ligand design by a build-up approach and genetic algorithmsearch in conformational space

Program to engineer peptides (PEP) is a build-up approach for ligand dockin g and design with implicit solvation. It requires the knowledge of a seed f rom which it iteratively grows polymeric ligands consisting of any type of amino acid, i.e., natural and/or nonnatural from a user-defined library. At every growing step, a genetic algorithm is used for conformational optimiz ation of the last added monomer in the rigid binding site. Pruning is perfo rmed at every growing step by selecting sequences according to binding ener gy with electrostatic solvation. PEP is applied to three members of the cas pase family of cysteine proteases using Asp at P-1 as seed. The optimal P-4 -P-2 peptide recognition motifs and variants thereof are docked correctly i n the active site (backbone root-mean-square deviation < 0.9 Angstrom). Mor eover, for each caspase, the P-4-P-2 sequences of potent aldehyde inhibitor s are ranked among the 15 hits with the most favorable PEP energy. (C) 2001 John Wiley & Sons, Inc.