Identification of Small-Molecule Inhibitors of Fibroblast Growth Factor 23 Signaling via In Silico Hot Spot Prediction and Molecular Docking to α-Klotho
Shih‐Hsien Liu, Zhousheng Xiao, Sambit Kumar Mishra, Julie C. Mitchell, Jeremy C. Smith, L. Darryl Quarles, Loukas Petridis
Abstract
) of 5.0 ± 0.23 μM. Molecular dynamics (MD) simulations of the ZINC12409120:α-Klotho complex starting from in silico docking poses reveal that the ligand exhibits contacts with residues on the KL1 domain, the KL1-KL2 linker, and the KL2 domain of α-Klotho simultaneously, thereby possibly disrupting the regular function of α-Klotho and impeding FGF23:α-Klotho interaction. ZINC12409120 is a candidate for lead optimization.
Topics & Concepts
KlothoDruggabilityDocking (animal)Fibroblast growth factor 23ChemistryTernary complexHypophosphatemiaFibroblast growth factorReceptorSmall moleculeFibroblast growth factor receptorIn silicoBiochemistryBiophysicsCalciumBiologyEndocrinologyMedicineEnzymeParathyroid hormoneKidneyNursingGeneOrganic chemistryParathyroid Disorders and TreatmentsBone health and treatmentsFibroblast Growth Factor Research