Title:

A Genetic Algorithm for Pharmacophore Elucidation

Author:

Gareth Jones
Arena Pharmaceuticals

Abstract:

A genetic algorithm (GA) has been developed for pharmacophore elucidation
and the superimposition of sets of flexible molecules.  This algorithm,
called GAPE (Genetic Algorithm for Pharmacophore Elucidation) is based on
the GASP program [1], but incorporates numerous improvements.  In
particular, many ideas used in the development of the docking program GOLD
[2] have been applied to the new algorithm. Additionally, GAPE does not
require that all molecules in the input set contain the pharmacophore.

The algorithm chooses one molecule to act as a template against which all
the other molecules are superimposed, in such a way that pharmacophore
features such as donor interaction points, acceptor atoms and ring centres
are overlaid.  Simultaneously, all structures are conformationally
searched.  The program incorporates a definition of hydrogen bonding
groups catalogued by Mills and Dean [3].  In addition to use in in-house
projects the algorithm has been evaluated on a number of publicly
available data-sets. 

1.	G. Jones, P. Willett and R. C. Glen, "A Genetic Algorithm for
Flexible Molecular Overlay and Pharmacophore Elucidation," Journal of
Computer-Aided Molecular Design 9 (1995) pp.532-549. 
2.	G. Jones, P. Willett, R. C. Glen, A. R. Leach and R. Taylor,
"Development and Validation of a Genetic Algorithm for Flexible
Docking," Journal of Molecular Biology 267 (1997) pp.727-748.
3.	J.E.J Mills and P.M. Dean, "Three-Dimensional Hydrogen-bond
Geometry and Probability Information from a Crystal Survey," Journal
of Computer-Aided Molecular Design 10 (1996) pp.607-622.