Proposal of a new binding orientation for non-peptide AT1 antagonists: homology modeling, docking and three-dimensional quantitative structure-activity relationship analysis.
A three-dimensional model of the AT1 receptor was constructed by means of a homology modeling procedure, using the X-ray structure of bovine rhodopsin as the initial template and taking into account the available site-directed mutagenesis data. The docking of losartan and its active metabolite EXP3174, followed by 1 ns of molecular dynamics (MD) simulation inserted into the phospholipid bilayer, suggested a different binding orientation for these antagonists from those previously proposed. Furthermore, the docking of several non-peptide antagonists was used as an alignment tool for the development of a three-dimensional quantitative structure-activity relationship (3D-QSAR) model, and the good results confirmed our binding hypothesis and the reliability of the model.
Tuccinardi
Tiziano
T
Dipartimento di Scienze Farmaceutiche, Università di Pisa, via Bonanno 6, 56126 Pisa, Italy.
Calderone
Vincenzo
V
Rapposelli
Simona
S
Martinelli
Adriano
A
D000595:Amino Acid Sequence; D047228:Angiotensin II Type 1 Receptor Blockers / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D002417:Cattle; D018360:Crystallography, X-Ray; D007093:Imidazoles / Q000737:chemistry; D008051:Lipid Bilayers / Q000737:chemistry; D019808:Losartan / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010743:Phospholipids / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D044140:Receptor, Angiotensin, Type 1 / Q000737:chemistry* / Q000235:genetics; D012243:Rhodopsin / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D013777:Tetrazoles / Q000737:chemistry
D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D008051:Lipid Bilayers; D010743:Phospholipids; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D012243:Rhodopsin; C066026:losartan carboxylic acid; D019808:Losartan