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Integrated approach to indentify novel P‐glycoprotein substrates and inhibitors
Author(s) -
Bahadduri Praveen,
Chang Cheng,
Ekins Sean,
Swaan Peter
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1188-b
Subject(s) - pharmacophore , in silico , chemistry , p glycoprotein , quantitative structure–activity relationship , virtual screening , computational biology , database search engine , combinatorial chemistry , database , stereochemistry , computer science , biochemistry , biology , information retrieval , multiple drug resistance , antibiotics , search engine , gene
The objective of the study was to identify novel P‐glycoprotein (P‐gp) ligands using pharmacophore and QSAR models derived from different subsets of ligands for P‐gp and to carry out in vitro testing of the ligands to demonstrate the predictive accuracy of pharmacophores. The efficacy of the pharmacophores as a database filter was assessed by developing two distinct P‐gp digoxin inhibition models and one P‐gp substrate model. 3 databases used, Database A, included P‐gp substrates and non‐substrates, Database B of widely prescribed drugs and Database C of commercially available Maybridge database and seeded with 105 known P‐gp substrates. Seven molecules were selected by different searching methods. Searching database A with all pharmacophores and using consistent metrics indicated that fast searching would be suitable to retrieve the most P‐gp ligands. Database B retrieved 40 drugs that were predicted to inhibit P‐gp of which 25 were identified as P‐gp ligands in the literature. A second inhibitor pharmacophore retrieved 68 drugs, of which 33 drugs were identified as known P‐gp ligands. Monolayer efflux and P‐gp ATPase activation were set up to evaluate these compounds. The P‐gp pharmacophore models identified 7 new compounds with affinity for P‐gp. Thus, the combined in silico and in vitro approach can be applied to rapidly identify molecules that have affinity for P‐gp during drug discovery.