| Abstract
| - We present an improved version of the program LEA developed to design organic molecules.Rational drug design involves finding solutions to large combinatorial problems for which anexhaustive search is impractical. Genetic algorithms provide a tool for the investigation ofsuch problems. New software, called LEA3D, is now able to conceive organic molecules bycombining 3D fragments. Fragments were extracted from both biological compounds and knowndrugs. A fitness function guides the search process in optimizing the molecules toward anoptimal value of the properties. The fitness function is build up by combining severalindependent property evaluations, including the score provided by the FlexX docking program.One application in de novo drug design is described. The example makes use of the structureof Mycobacterium tuberculosis thymidine monophosphate kinase to generate analogues of oneof its natural substrates. Among 22 tested compounds, 17 show inhibitory activity in themicromolar range.
|
