Non-peptide angiotensin II receptor antagonists: chemical feature based pharmacophore identification.
Chemical feature based pharmacophore models were elaborated for angiotensin II receptor subtype 1 (AT(1)) antagonists using both a quantitative and a qualitative approach (Catalyst HypoGen and HipHop algorithms, respectively). The training sets for quantitative model generation consisted of 25 selective AT(1) antagonists exhibiting IC(50) values ranging from 1.3 nM to 150 microM. Additionally, a qualitative pharmacophore hypothesis was derived from multiconformational structure models of the two highly active AT(1) antagonists 4u (IC(50) = 0.2 nM) and 3k (IC(50) = 0.7 nM). In the case of the quantitative model, the best pharmacophore hypothesis consisted of a five-features model (Hypo1: seven points, one hydrophobic aromatic, one hydrophobic aliphatic, a hydrogen bond acceptor, a negative ionizable function, and an aromatic plane function). The best qualitative model consisted of seven features (Hypo2: 11 points, two aromatic rings, two hydrogen bond acceptors, a negative ionizable function, and two hydrophobic functions). The obtained pharmacophore models were validated on a wide set of test molecules. They were shown to be able to identify a range of highly potent AT(1) antagonists, among those a number of recently launched drugs and some candidates presently undergoing clinical tests and/or development phases. The results of our study provide confidence for the utility of the selected chemical feature based pharmacophore models to retrieve structurally diverse compounds with desired biological activity by virtual screening.
Krovat
Eva M
EM
Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Innsbruck, Innrain 52a, A-6020 Innsbruck, Austria. eva.krovat@uibk.ac.at
Langer
Thierry
T
D000179:Acrylates / Q000737:chemistry; D000465:Algorithms; D000804:Angiotensin II / Q000737:chemistry* / Q000378:metabolism; D001713:Biphenyl Compounds / Q000737:chemistry; D016208:Databases, Factual; D007093:Imidazoles / Q000737:chemistry; D007783:Lactones / Q000737:chemistry; D019808:Losartan / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D011725:Pyridines / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000737:chemistry* / Q000378:metabolism; D013450:Sulfones; D013777:Tetrazoles / Q000737:chemistry; D013876:Thiophenes
D000179:Acrylates; D001713:Biphenyl Compounds; D007093:Imidazoles; D007783:Lactones; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D013450:Sulfones; D013777:Tetrazoles; D013876:Thiophenes; C084927:forasartan; C116926:rofecoxib; D000804:Angiotensin II; C064482:EXP7711; C068373:eprosartan; D019808:Losartan