Carolyn D Dzierba,
Andrew J Tebben,
Richard G Wilde,
Amy G Takvorian,
Maria Rafalski,
Padmaja Kasireddy-Polam, John D Klaczkiewicz,
Anthony D Pechulis,
Amy L Davis,
Mark P Sweet,
Alex M Woo,
Zhicai Yang,
Sarah M Ebeltoft,
Thaddeus F Molski,
Ge Zhang,
Robert C Zaczek,
George L Trainor,
Andrew P Combs,
Paul J Gilligan
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ABSTRACT: The CRF antagonist pharmacophore is a heterocyclic ring bearing a critical hydrogen-bond acceptor nitrogen and an orthogonal aromatic ring. CRFR1 antagonists have shown a 40-fold and 200-fold loss in potency against the CRFR1 H199V and M276I mutant receptors, suggesting key interactions with these residues. We have derived a two component computational model that correlates CRFR1 binding affinity within the reported series to antagoinst/H199 complexation energy and M276 hydrophobic contacts.
Journal of Medicinal Chemistry 05/2007; 50(9):2269-72. · 5.25 Impact Factor
