Fuzzy Pharmacophore Models from Molecular Alignments for Correlation-Vector-Based Virtual Screening
- 11 August 2004
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 47 (19) , 4653-4664
- https://doi.org/10.1021/jm031139y
Abstract
A pharmacophore-based approach for compiling focused screening libraries is presented. It integrates information from three-dimensional molecular alignments into correlation vector-based database screening. The pharmacophore model is represented by a number of spheres of Gaussian-distributed feature densities. Different degrees of “fuzziness” can be introduced to influence the model's resolution. Transformation of this pharmacophore representation into a correlation vector results in a vector of feature probabilities which can be utilized for rapid virtual screening of compound databases or virtual libraries. The approach was validated by retrospective screening for cyclooxygenase 2 (COX-2) and thrombin ligands. A variety of models with different degrees of fuzziness were calculated and tested for both classes of molecules. Best performance was obtained with pharmacophore models reflecting an intermediate degree of fuzziness, yielding an enrichment factor of up to 39 for the first 1% of the ranked database. Appropriately weighted fuzzy pharmacophore models performed better in retrospective screening than similarity searching using only a single query molecule. The new pharmacophore method was shown to complement existing approaches.Keywords
This publication has 11 references indexed in Scilit:
- Comparison of correlation vector methods for ligand-based similarity searchingJournal of Computer-Aided Molecular Design, 2003
- Collection of Bioactive Reference Compounds for Focused Library DesignQSAR & Combinatorial Science, 2003
- Neighborhood Behavior. Fuzzy Molecular Descriptors and their Influence on the Relationship between Structural Similarity and Property SimilarityQSAR & Combinatorial Science, 2003
- Identification of Novel Cyclooxygenase-2 Selective Inhibitors Using Pharmacophore ModelsJournal of Medicinal Chemistry, 2002
- A comparison of the pharmacophore identification programs: Catalyst, DISCO and GASPJournal of Computer-Aided Molecular Design, 2002
- Design, synthesis and structure–activity relationship of a series of arginine aldehyde factor Xa inhibitors. Part 1: structures based on the ( d )-Arg-Gly-Arg tripeptide sequenceBioorganic & Medicinal Chemistry Letters, 2000
- “Scaffold-Hopping” by Topological Pharmacophore Search: A Contribution to Virtual ScreeningAngewandte Chemie International Edition in English, 1999
- New 4-Point Pharmacophore Method for Molecular Similarity and Diversity Applications: Overview of the Method and Applications, Including a Novel Approach to the Design of Combinatorial Libraries Containing Privileged SubstructuresJournal of Medicinal Chemistry, 1999
- The first highly potent and selective non-peptide neuropeptide Y Y1 receptor antagonist: BIBP3226European Journal of Pharmacology, 1994
- Chemical Function Queries for 3D Database SearchJournal of Chemical Information and Computer Sciences, 1994