title: Pharmacophore mapping of a series of pyrrolopyrimidines, indolopyrimidines and their congeners as multidrug-resistance-associated protein (MRP1) modulators.
abstract: Pharmacophore mapping studies were undertaken for a series of molecules belonging to pyrrolopyrimidines, indolopyrimidines and their congeners as multidrug resistance-associated protein (MRP1) modulators. A five-point pharmacophore with two hydrogen bond acceptors (A), one lipophilic/hydrophobic group (H), one positive ionic feature (P) and one aromatic ring (R) as pharmacophoric features was developed. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a correlation coefficient of r2 = 0.799 for training set molecules. The model generated showed excellent predictive power, with a correlation coefficient Q2 = 0.679 for an external test set of 20 molecules. The pharmacophore was further validated using four structurally diverse compounds with MRP1 modulatory activity. These compounds mapped well onto four of the five features of the pharmacophore. The pharmacophore proposed here was then utilised for the successful retrieval of active molecules with diverse chemotypes from database search. The geometry and features of pharmacophore are expected to be useful for the design of selective MRP1 inhibitors.
authors.affiliation: Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, University of Mumbai, Matunga (E), Mumbai, 400019, India.
authors.forename: Nilesh R
authors.initials: NR
authors.lastname: Tawari
authors.forename: Seema
authors.initials: S
authors.lastname: Bag
authors.forename: Mariam S
authors.initials: MS
authors.lastname: Degani
mesh_terms: D003198:Computer Simulation; D006801:Humans; D006860:Hydrogen Bonding; D007211:Indoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007555:Isoxazoles / Q000494:pharmacology; D008958:Models, Molecular; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000187:drug effects*; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D015363:Quinolones / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D012838:Silymarin / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology
chemical_list: D007211:Indoles; D007555:Isoxazoles; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011743:Pyrimidines; D011758:Pyrroles; D015363:Quinolones; D011810:Quinoxalines; D012838:Silymarin; D013449:Sulfonamides; D013876:Thiophenes; C532625:LY 402913; C515097:dehydrosilybin; C402711:LY 329146; C421109:multidrug resistance-associated protein 1