Molecular docking study of the interactions between the thioesterase domain of human fatty acid synthase and its ligands

Human fatty acid synthase (hFAS) thioesterase domain (TE) is an attractive drug target to treat obesity and cancer. On the basis of the recently published crystal structure of TE domain of hFAS, we performed molecular surface analysis and docking study to characterize the molecular interactions between the enzyme and its various ligands. Surface analysis identified the ligand‐binding pocket of TE domain that encompasses the catalytic triad of Ser2308, His2481, Asp2338. Docking of palmitate, the main biological product of hFAS, into this pocket revealed the ligand‐binding mode, in which the hydrophobic interactions are the dominant driving forces. The catalytic mechanism of TE domain can also be well explained based on the generated TE‐palmitate complex structure. Moreover, the comparison of the binding modes of five fatty acids with chain lengths ranging from 12 to 20 carbons confirmed that the ligand binding pocket of TE domain is a decisive factor in chain length specificity. In addition, docking of two known TE inhibitors, c75 and orlistat revealed the pharmacophore of these hFAS TE inhibitors, which will prove useful in structure‐based drug design against this important target. Proteins 2008. © 2007 Wiley‐Liss, Inc.

[1]  S. Wakil,et al.  Fatty acid synthase, a proficient multifunctional enzyme. , 1989, Biochemistry.

[2]  Daniel A Erlanson,et al.  Tethering: fragment-based drug discovery. , 2004, Annual review of biophysics and biomolecular structure.

[3]  A. Rendina,et al.  Characterization of the inactivation of rat fatty acid synthase by C75: inhibition of partial reactions and protection by substrates. , 2005, The Biochemical journal.

[4]  Wendy A. Warr,et al.  Fragment-based drug discovery , 2009, J. Comput. Aided Mol. Des..

[5]  E. Jaffee,et al.  Fatty acid synthase inhibitors are chemopreventive for mammary cancer in neu-N transgenic mice , 2005, Oncogene.

[6]  Jie Liang,et al.  CASTp: Computed Atlas of Surface Topography of proteins , 2003, Nucleic Acids Res..

[7]  Andrzej Witkowski,et al.  Structural and functional organization of the animal fatty acid synthase. , 2003, Progress in lipid research.

[8]  H. Edelsbrunner,et al.  Anatomy of protein pockets and cavities: Measurement of binding site geometry and implications for ligand design , 1998, Protein science : a publication of the Protein Society.

[9]  S. Wakil,et al.  On the question of half- or full-site reactivity of animal fatty acid synthetase. , 1984, The Journal of biological chemistry.

[10]  Richard D. Taylor,et al.  Improved protein–ligand docking using GOLD , 2003, Proteins.

[11]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[12]  B. Chakravarty,et al.  Human fatty acid synthase: structure and substrate selectivity of the thioesterase domain. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Christian Senger,et al.  Representation of target-bound drugs by computed conformers: implications for conformational libraries , 2006, BMC Bioinformatics.

[14]  S. Chirala,et al.  Structure and function of animal fatty acid synthase , 2004, Lipids.

[15]  Stuart Smith.  The animal fatty acid synthase: one gene, one polypeptide, seven enzymes , 1994, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[16]  P. Hajduk,et al.  Discovering High-Affinity Ligands for Proteins: SAR by NMR , 1996, Science.

[17]  G. Ronnett,et al.  C75, a Fatty Acid Synthase Inhibitor, Reduces Food Intake via Hypothalamic AMP-activated Protein Kinase* , 2004, Journal of Biological Chemistry.

[18]  M. C. Archer,et al.  Fatty acid synthase is a potential molecular target for the chemoprevention of breast cancer. , 2004, Carcinogenesis.

[19]  S. Chirala,et al.  Characterization of recombinant thioesterase and acyl carrier protein domains of chicken fatty acid synthase expressed in Escherichia coli. , 1989, Journal of Biological Chemistry.

[20]  M. Lane,et al.  Effect of centrally administered C75, a fatty acid synthase inhibitor, on ghrelin secretion and its downstream effects. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[21]  Jeffrey W. Smith,et al.  Orlistat Is a Novel Inhibitor of Fatty Acid Synthase with Antitumor Activity , 2004, Cancer Research.

[22]  S. Wakil,et al.  The architecture of the animal fatty acid synthetase. II. Separation of the core and thioesterase functions and determination of the N-C orientation of the subunit. , 1983, The Journal of biological chemistry.