Discovery and optimization of highly ligand-efficient oxytocin receptor antagonists using structure-based drug design.
A novel oxytocin antagonist was identified by 'scaffold-hopping' using Cresset FieldScreen molecular field similarity searching. A single cycle of optimization driven by an understanding of the key pharmacophoric elements required for activity led to the discovery of a potent, selective and highly ligand-efficient oxytocin receptor antagonist. Selectivity over vasopressin receptors was rationalized based on differences in the structure of the natural ligands.
Bellenie
Benjamin R
BR
GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park (North), Coldharbour Road, Harlow, Essex CM19 5AD, England, United Kingdom. ben.r.bellenie@gsk.com
Barton
Nicholas P
NP
Emmons
Amanda J
AJ
Heer
Jag P
JP
Salvagno
Cristian
C
D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D005260:Female; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008956:Models, Chemical; D008968:Molecular Conformation; D007752:Obstetric Labor, Premature / Q000188:drug therapy; D010121:Oxytocin / Q000737:chemistry*; D011247:Pregnancy; D018045:Receptors, Oxytocin / Q000037:antagonists & inhibitors*; D017483:Receptors, Vasopressin / Q000737:chemistry*; D014667:Vasopressins / Q000737:chemistry*; D014668:Vasotocin / Q000031:analogs & derivatives / Q000737:chemistry
D008024:Ligands; D018045:Receptors, Oxytocin; D017483:Receptors, Vasopressin; C047046:atosiban; D014667:Vasopressins; D010121:Oxytocin; D014668:Vasotocin