PRO-LIGAND - AN APPROACH TO DE-NOVO MOLECULAR DESIGN .3. A GENETIC ALGORITHM FOR STRUCTURE REFINEMENT

Recently, the development of computer programs which permit the de nov o design of molecular structures satisfying a set of steric and chemic al constraints has become a burgeoning area of research and many opera tional systems have been reported in the literature. Experience with P RO_LIGAND - the de novo design methodology embodied in our in-house mo lecular design and simulation system PROMETHEUS - has suggested that t he addition of a genetic algorithm (GA) structure refinement procedure can 'add value' to an already useful tool. Starting with the set of d esigned molecules as an initial population, the GA can combine feature s from both high- and low-scoring structures and, over a number of gen erations, produce individuals of better score than any of the starting structures. This paper describes how we have implemented such a proce dure and demonstrates its efficacy in improving two sets of molecules generated by different de novo design projects.