The selection and design of GPCR ligands: from concept to the clinic.
Virtual screening methods using structure-based, pharmacophore-based and descriptor based protocols may be used to identify ligands for the G-protein coupled receptor target family. A complementary approach is the synthesis and screening of compound libraries designed using privileged motifs and/or based on validated hit molecules. A virtual screening approach based on molecular docking performed with GOLD using a templated homology model and a consensus scoring procedure can identify vasopressin 1a receptor antagonists. In a separate project a library design and synthesis approach based around validated hit GPCR ligands led to the identification of potent oxytocin antagonists. Subsequent optimisation of the initial library compounds has provided compounds that are now being evaluated in the clinic for the treatment of preterm labour.
Ashton
Mark
M
Evotec OAI, 151 Milton Park, Abingdon, Oxfordshire OX14 4SD, UK. mark.whittaker@evotecoai.com
Charlton
Michael H
MH
Schwarz
Matthias K
MK
Thomas
Russell J
RJ
Whittaker
Mark
M
D000818:Animals; D003198:Computer Simulation; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D010121:Oxytocin / Q000037:antagonists & inhibitors; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects*; D013329:Structure-Activity Relationship
D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D010121:Oxytocin