A genetic algorithm for structure-based de novo design

Authors: Pegg S.C.-H.¹; Haresco J.J.¹; Kuntz I.D.²

Source: Journal of Computer-Aided Molecular Design, Volume 15, Number 10, October 2001 , pp. 911-933(23)

Publisher: Springer

Buy & download fulltext article:

Price: $47.00 plus tax (Refund Policy)

Abstract:

Genetic algorithms have properties which make them attractive in de novo drug design. Like other de novo design programs, genetic algorithms require a method to reduce the enormous search space of possible compounds. Most often this is done using information from known ligands. We have developed the ADAPT program, a genetic algorithm which uses molecular interactions evaluated with docking calculations as a fitness function to reduce the search space. ADAPT does not require information about known ligands. The program takes an initial set of compounds and iteratively builds new compounds based on the fitness scores of the previous set of compounds. We describe the particulars of the ADAPT algorithm and its application to three well-studied target systems. We also show that the strategies of enhanced local sampling and re-introducing diversity to the compound population during the design cycle provide better results than conventional genetic algorithm protocols.

Keywords: ADAPT; combinatorial chemistry; de novo design; DOCK; genetic algorithm

Language: English

Document Type: Regular paper

Affiliations: 1: Department of Pharmaceutical Chemistry and Program in Biological and Medical Informatics, University of California, San Francisco, San Francisco, CA 94143, USA 2: E-mail: kuntz@cgl.ucsf.edu

Publication date: 2001-10-01