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

Program to engineer peptides (PEP) is a build-up approach for ligand docking and design with implicit solvation. It requires the knowledge of a seed from 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 optimization of the last added monomer in the rigid binding site. Pruning is performed at every growing step by selecting sequences according to binding energy with electrostatic solvation. PEP is applied to three members of the caspase 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 in the active site (backbone root-mean-square deviation < 0.9 Angstrom). Moreover, for each caspase, the P(4)-P(2) sequences of potent aldehyde inhibitors are ranked among the 15 hits with the most favorable PEP energy. (C) 2001 John Wiley & Sons, Inc.