Evaluation of small-molecule modulators of the luteinizing hormone/choriogonadotropin and thyroid stimulating hormone receptors: structure-activity relationships and selective binding patterns.
The substituted thieno[2,3-d]pyrimidine 3 (Org 41841), a partial agonist for the luteinizing hormone/choriogonadotropin receptor (LHCGR) and the closely related thyroid-stimulating hormone receptor (TSHR), was fundamentally altered, and the resulting analogues were analyzed for their potencies, efficacies, and specificities at LHCGR and TSHR. Chemical modification of the parent compound combined with prior mutagenesis of TSHR provided compelling experimental evidence in support of computational models of 3 binding to TSHR and LHCGR within their transmembrane cores. Biochemical analysis of a specific modification to the chemical structure of 3 provides additional evidence of a H-bond between the ligand and a glutamate residue in transmembrane helix 3, which is conserved in both receptors. Several key interactions were surveyed to determine their respective biochemical roles in terms of both van der Waals dimensions and hydrogen bond capacity and the respective relationship to biological activity.
Moore
Susanna
S
Chemical Biology Core Facility, Clinical Endocrinology Branch, and Computational Chemistry Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Jaeschke
Holger
H
Kleinau
Gunnar
G
Neumann
Susanne
S
Costanzi
Stefano
S
Jiang
Jian-kang
JK
Childress
John
J
Raaka
Bruce M
BM
Colson
Anny
A
Paschke
Ralf
R
Krause
Gerd
G
Thomas
Craig J
CJ
Gershengorn
Marvin C
MC
D001665:Binding Sites; D006063:Chorionic Gonadotropin / Q000819:agonists / Q000737:chemistry*; D006860:Hydrogen Bonding; D008024:Ligands; D007986:Luteinizing Hormone / Q000819:agonists / Q000737:chemistry*; D008958:Models, Molecular; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry; D011989:Receptors, Thyrotropin / Q000819:agonists / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry
D006063:Chorionic Gonadotropin; D008024:Ligands; C510603:Org 41841; D011743:Pyrimidines; D011989:Receptors, Thyrotropin; D013876:Thiophenes; D007986:Luteinizing Hormone