Investigations of neurotrophic inhibitors of FK506 binding protein via Monte Carlo simulations.
The binding and solution-phase properties of six inhibitors of FK506 binding protein (FKBP12) were investigated using free energy perturbation techniques in Monte Carlo statistical mechanics simulations. These nonimmunosuppressive molecules are of current interest for their neurotrophic activity when bound to FKBP12 as well as for their potential as building blocks for chemical inducers of protein dimerization. Relative binding affinities were computed and analyzed for ligands differing by a phenyl ring, an external phenyl or pyridyl substituent, and a pipecolyl or prolyl ring. Such results are, in general, valuable for inhibitor optimization and, in the present case, bring into question some of the previously reported binding data.
Lamb
M L
ML
Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, USA.
Jorgensen
W L
WL
D000818:Animals; D001555:Benzene Derivatives / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D002645:Chickens; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D020104:Immunophilins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D009010:Monte Carlo Method; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism; D016559:Tacrolimus / Q000378:metabolism*; D022021:Tacrolimus Binding Proteins; D013816:Thermodynamics
D001555:Benzene Derivatives; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D008024:Ligands; D011725:Pyridines; D022021:Tacrolimus Binding Proteins; D020104:Immunophilins; D019696:Peptidylprolyl Isomerase; D016559:Tacrolimus