title: GRID-based three-dimensional pharmacophores I: FLAPpharm, a novel approach for pharmacophore elucidation.
abstract: Pharmacophore elucidation approaches are routinely used in drug discovery, primarily with the aim of determining the three-dimensional arrangement of common features shared by ligands interacting at the site of interest; these features can then be used to investigate the structure-activity relationship between the ligands and also to screen for other molecules possessing the relevant features. Here we present a novel approach based on GRID molecular interaction fields and the derivative method FLAP that has been previously described, which provides a common reference framework to compare both small molecule ligands and macromolecular protein targets. Unlike classical pharmacophore elucidation approaches that extract simplistic molecular features, determine those which are common across the data set, and use these features to align the structures, FLAPpharm first aligns the structures and subsequently extracts the common interacting features in terms of their molecular interaction fields, pseudofields, and atomic points, representing the common pharmacophore as a more comprehensive pharmacophoric pseudomolecule. The approach is applied to a number of data sets to investigate performance in terms of reproducing the X-ray crystallography-based alignment, in terms of its discriminatory ability when applied to virtual screening and also to illustrate its ability to explain alternative binding modes. In part two of this publication, a comprehensive benchmark data set for pharmacophore elucidation is presented and the performance of FLAPpharm discussed.
authors.affiliation: Molecular Discovery Limited, 215 Marsh Road, Pinner, Middlesex, London HA5 5NE, United Kingdom. simon@moldiscovery.com
authors.forename: Simon
authors.initials: S
authors.lastname: Cross
authors.forename: Massimo
authors.initials: M
authors.lastname: Baroni
authors.forename: Laura
authors.initials: L
authors.lastname: Goracci
authors.forename: Gabriele
authors.initials: G
authors.lastname: Cruciani
mesh_terms: D000465:Algorithms; D001407:Bacillus / Q000737:chemistry; D001665:Binding Sites; D001688:Biological Products / Q000737:chemistry*; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2 / Q000737:chemistry*; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry*; D013820:Thermolysin / Q000737:chemistry*; D013917:Thrombin / Q000737:chemistry*
chemical_list: D001688:Biological Products; D008024:Ligands; D013762:Tetrahydrofolate Dehydrogenase; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D013917:Thrombin; D013820:Thermolysin