Probing the fibrate binding specificity of rat liver fatty acid binding protein.
Liver-fatty acid binding protein (L-FABP) is found in high levels in enterocytes and is involved in cytosolic solubilization of fatty acids. In addition, L-FABP has been shown to bind endogenous and exogenous lipophilic compounds, suggesting that it may also play a role in modulating their absorption and disposition within enterocytes. Previously, we have described binding of L-FABP to a range of drugs, including a series of fibrates. In the present study, we have generated structural models of L-FABP-fibrate complexes and undertaken thermodynamic analysis of the binding of fibrates containing either a carboxylic acid or ester functionality. Analysis of the current data reveals that both the location and the energetics of binding are different for fibrates that contain a carboxylate compared to those that do not. As such, the data presented in this study suggest potential mechanisms that underpin molecular recognition and dictate specificity in the interaction between fibrates and L-FABP.
Chuang
Sara
S
Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
Velkov
Tony
T
Horne
James
J
Wielens
Jerome
J
Chalmers
David K
DK
Porter
Christopher J H
CJ
Scanlon
Martin J
MJ
D000818:Animals; D001665:Binding Sites; D002264:Carboxylic Acids / Q000737:chemistry; D002995:Clofibric Acid / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D004952:Esters / Q000737:chemistry; D050556:Fatty Acid-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D011345:Fenofibrate / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008024:Ligands; D008099:Liver / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D051381:Rats; D013050:Spectrometry, Fluorescence; D013379:Substrate Specificity; D013696:Temperature; D013816:Thermodynamics
D002264:Carboxylic Acids; D004952:Esters; D050556:Fatty Acid-Binding Proteins; D000960:Hypolipidemic Agents; D008024:Ligands; D002995:Clofibric Acid; C006012:fenofibric acid; D011345:Fenofibrate