title: Modeling and synthesis of non-cyclic derivatives of GPI-1046 as potential FKBP ligands with neurotrophic properties.
abstract: Prompted by the therapeutic potential of the neuroimmunophilin FK506-binding protein (FKBP) ligand, GPI-1046, in the treatment of nerve injuries and neurodegenerative diseases, a novel series of non-cyclic derivatives of GPI-1046 were designed and synthesized. Computer modeling analysis revealed that these relatively linear derivatives could energy-favorably bind to FKBP12 with an analogous binding mode to GPI-1046. The neurotrophic activity of the target compounds was assessed in chick dorsal root ganglion (DRG) cultures. As a result, 6 out of 11 test compounds at either or both concentrations of 1 pM and 100 pM significantly promoted neurite outgrowth in DRGs in the presence of 0.15 ng/ml nerve growth factor (NGF). Compound 5c at 100 pM exhibited the greatest neurotrophic effect in promoting both the number and length of neurite processes. However, in the absence of exogenously added NGF, all test compounds, including GPI-1046, failed to afford any positive effect on DRGs. This study suggests the intriguing potential of these compounds for further investigation.
authors.affiliation: Laboratory of Computer-Aided Drug Design and Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing, China. liqinz@usc.edu
authors.forename: Liqin
authors.initials: L
authors.lastname: Zhao
authors.forename: Hongying
authors.initials: H
authors.lastname: Liu
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.forename: Song
authors.initials: S
authors.lastname: Li
mesh_terms: D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002642:Chick Embryo; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*; D013302:Streptomyces / Q000378:metabolism; D016559:Tacrolimus / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000737:chemistry*
chemical_list: C104949:GPI 1046; D008024:Ligands; D011759:Pyrrolidines; D022021:Tacrolimus Binding Proteins; D016559:Tacrolimus