Molecular Docking Analysis Identifies Potential Antagonists of Misregulated Gsα Proteins

Abstract

McCune-Albright Syndrome (MAS) is a genetic disorder caused by GTPase deficient alleles of Gsα. This disease is characterized by hyperendocrinopathies, skin hyperpigmentation, and polyostotic fibrous dysplasia of bone. While the endocrine disorders can be managed with drugs, the bone disease has no pharmacological treatment, only a path of painful and often unsuccessful orthopedic surgeries. A small molecule inhibitor that is a specific antagonist to the mutant Gs isoform would be of great benefit to MAS patients. Previous work in the lab showed mutations at R231, a surface residue near the GTP-binding site, suppressed the constitutive activity of all MAS-associated mutations in Gs (R201H, R201C, R201S) and partially suppressed the constitutive activity of a Q227L mutation in Gs. Molecules were docked in silico to the R231 region, identifying several molecules with potential to bind to the suppressor site. Transiently transfected HEK cells overexpressing Gs-R201H were treated with each of 18 candidate molecules. Significant reduction in basal cAMP was observed in the presence of either 6-oxo-N-{[2-(pyrrolidin-1-yl)pyridin-4-yl]methyl}-1,6-dihydropyridazine-3-carboxamide or N-{[3-(3-methylphenyl)phenyl]methyl}-6-oxo-1,6-dihydropyridazine-3-carboxamide, while cells transfected with wild-type Gs constructs exhibited no decrease in basal cAMP levels when treated with these compounds. Thus, these compounds may serve as leads for the development of drugs for this rare disease. This work was Supported by NIH grant 1R15ED020190-01