title: Genetic algorithm for the design of molecules with desired properties.
abstract: The design of molecules with desired properties is still a challenge because of the largely unpredictable end results. Computational methods can be used to assist and speed up this process. In particular, genetic algorithms have proved to be powerful tools with a wide range of applications, e.g. in the field of drug development. Here, we propose a new genetic algorithm that has been tailored to meet the demands of de novo drug design, i.e. efficient optimization based on small training sets that are analyzed in only a small number of design cycles. The efficiency of the design algorithm was demonstrated in the context of several different applications. First, RNA molecules were optimized with respect to folding energy. Second, a spinglass was optimized as a model system for the optimization of multiletter alphabet biopolymers such as peptides. Finally, the feasibility of the computer-assisted molecular design approach was demonstrated for the de novo construction of peptidic thrombin inhibitors using an iterative process of 4 design cycles of computer-guided optimization. Synthesis and experimental fitness determination of only 600 different compounds from a virtual library of more than 10(17) molecules was necessary to achieve this goal.
authors.affiliation: Abteilung fuer Molekulare Genetik und Praeparative Molekularbiologie, Institut für Mikrobiologie und Genetik, Grisebachstr. 8, 37077 Goettingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kamphausen
authors.forename: Nils
authors.initials: N
authors.lastname: Höltge
authors.forename: Frank
authors.initials: F
authors.lastname: Wirsching
authors.forename: Corinna
authors.initials: C
authors.lastname: Morys-Wortmann
authors.forename: Daniel
authors.initials: D
authors.lastname: Riester
authors.forename: Ruediger
authors.initials: R
authors.lastname: Goetz
authors.forename: Marcel
authors.initials: M
authors.lastname: Thürk
authors.forename: Andreas
authors.initials: A
authors.lastname: Schwienhorst
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D001483:Base Sequence; D003198:Computer Simulation; D017076:Computer-Aided Design; D015195:Drug Design; D066298:In Vitro Techniques; D007700:Kinetics; D008957:Models, Genetic; D009690:Nucleic Acid Conformation; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D012313:RNA / Q000737:chemistry / Q000235:genetics; D012985:Software Design; D013917:Thrombin / Q000037:antagonists & inhibitors
chemical_list: D019151:Peptide Library; D010455:Peptides; D012313:RNA; D013917:Thrombin