Abstract
X-ray crystal structural determination of FABP4 in complex with four inhibitors revealed the binding modes of the complexes, and the interactions between FABP4 and the inhibitors were analyzed. The detailed structure–activity relationship (SAR) could not be explained in terms of these crystal structural observations. Therefore, the interactions between FABP4 and the inhibitors were analyzed in more detail using fragment molecular orbital (FMO) method. This analysis revealed that the total interfragment interaction energies between FABP4 and each inhibitor correlated with the ranking of the Ki value for the four inhibitors. Furthermore, the interactions between each inhibitor and specific amino acid residues in FABP4 were identified. The oxygen atom of Lys58 in FABP4 was found to be very important for strong inhibitor–protein interactions. These results might provide useful information for the development of novel potent FABP4 inhibitors.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
RCSB PDB Annual Report 2016
Mazanetz MP, Ichihara O, Law RJ, Whittaker M (2011) Prediction of cyclin-dependent kinase 2 inhibitor potency using the fragment molecular orbital method. J Cheminform 3(1):1–15
Kitaura K, Ikeo E, Asada T, Nakano T, Uebayasi M (1999) Fragment molecular orbital method: an approximate computational method for large molecules. Chem Phys Lett 313:701–706
Fedorov DG, Kitaura K (2007) Extending the power of quantum chemistry to large systems with the fragment molecular orbital method. J Phys Chem a 111(30):6904–6914
Fedorov DG, Nagata T, Kitaura K (2012) Exploring chemistry with the fragment molecular orbital method. Phys Chem Chem Phys 14(21):7562–7577
Gordon MS, Fedorov DG, Pruitt SR, Slipchenko LV (2012) Fragmentation methods: a route to accurate calculations on large systems. Chem Rev 112(1):632–672
Furuhashi M, Hotamisligil GS (2008) Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. Nat Rev Drug Discov 7(6):489–503
Hotamisligil GS, Johnson RS, Distel RJ, Ellis R, Papaioannou VE, Spiegelman BM (1996) Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein. Science 274(5291):1377–1379
Uysal KT, Scheja L, Wiesbrock SM, Bonner-Weir S, Hotamisligil GS (2000) Improved glucose and lipid metabolism in genetically obese mice lacking aP2. Endocrinology 141(9):3388–3396
Makowski L, Boord JB, Maeda K, Babaev VR, Uysal KT, Morgan MA, Parker RA, Suttles J, Fazio S, Hotamisligil GS, Linton MF (2001) Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis. Nat Med 7(6):699–705
Furuhashi M, Tuncman G, Gorgun CZ, Makowski L, Atsumi G, Vaillancourt E, Kono K, Babaev VR, Fazio S, Linton MF, Sulsky R, Robl JA, Parker RA, Hotamisligil GS (2007) Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2. Nature 447(7147):959–965
Lehmann F, Haile S, Axen E, Medina C, Uppenberg J, Svensson S, Lundback T, Rondahl L, Barf T (2004) Discovery of inhibitors of human adipocyte fatty acid-binding protein, a potential type 2 diabetes target. Bioorg Med Chem Lett 14(17):4445–4448
Ringom R, Axen E, Uppenberg J, Lundback T, Rondahl L, Barf T (2004) Substituted benzylamino-6-(trifluoromethyl)pyrimidin-4(1H)-ones: a novel class of selective human A-FABP inhibitors. Bioorg Med Chem Lett 14(17):4449–4452
Sulsky R, Magnin DR, Huang Y, Simpkins L, Taunk P, Patel M, Zhu Y, Stouch TR, Bassolino-Klimas D, Parker R, Harrity T, Stoffel R, Taylor DS, Lavoie TB, Kish K, Jacobson BL, Sheriff S, Adam LP, Ewing WR, Robl JA (2007) Potent and selective biphenyl azole inhibitors of adipocyte fatty acid binding protein (aFABP). Bioorg Med Chem Lett 17(12):3511–3515
Barf T, Lehmann F, Hammer K, Haile S, Axen E, Medina C, Uppenberg J, Svensson S, Rondahl L, Lundback T (2009) N-Benzyl-indolo carboxylic acids: Design and synthesis of potent and selective adipocyte fatty-acid binding protein (A-FABP) inhibitors. Bioorg Med Chem Lett 19(6):1745–1748
Hertzel AV, Hellberg K, Reynolds JM, Kruse AC, Juhlmann BE, Smith AJ, Sanders MA, Ohlendorf DH, Suttles J, Bernlohr DA (2009) Identification and characterization of a small molecule inhibitor of Fatty Acid binding proteins. J Med Chem 52(19):6024–6031
Marr E, Tardie M, Carty M, Brown Phillips T, Wang IK, Soeller W, Qiu X, Karam G (2006) Expression, purification, crystallization and structure of human adipocyte lipid-binding protein (aP2). Acta Crystallogr Sect F Struct Biol Cryst Commun 62(Pt 11):1058–1060
Ory J, Kane CD, Simpson MA, Banaszak LJ, Bernlohr DA (1997) Biochemical and crystallographic analyses of a portal mutant of the adipocyte lipid-binding protein. J Biol Chem 272:9793–9801
Ory JJ, Banaszak LJ (1999) Studies of the ligand binding reaction of adipocyte lipid binding protein using the fluorescent probe 1, 8-anilinonaphthalene-8-sulfonate. Biophys J 77(2):1107–1116
Ory JJ, Mazhary A, Kuang H, Davies RR, Distefano MD, Banaszak LJ (1998) Structural characterization of two synthetic catalysts based on adipocyte lipid-binding protein. Protein Eng 11(4):253–261
Lalonde JM, Bernlohr DA, Banaszak LJ (1994) X-ray crystallographic structures of adipocyte lipid-binding protein complexed with palmitate and hexadecanesulfonic acid. Properties of Cavity Binding Sites. Biochemistry 33(16):4885–4895
Lalonde JM, Levenson MA, Roe JJ, Bernlohr DA, Banaszak LJ (1994) Adipocyte lipid-binding protein complexed with arachidonic acid. Titration calorimetry and X-ray crystallographic studies. J Biol Chem 269(41):25339–25347
Xu Z, Bernlohr DA, Banaszak LJ (1993) The adipocyte lipid-binding protein at 1.6-A resolution. Crystal structures of the apoprotein and with bound saturated and unsaturated fatty acids. J Biol Chem 268(11):7874–7884
Xu Z, Bernlohr DA, Banaszak LJ (1992) Crystal structure of recombinant murine adipocyte lipid-binding protein. Biochemistry 31(13):3484–3492
Xu ZH, Buelt MK, Banaszak LJ, Bernlohr DA (1991) Expression, purification, and crystallization of the adipocyte lipid binding protein. J Biol Chem 266(22):14367–14370
Van Dongen MJ, Uppenberg J, Svensson S, Lundback T, Akerud T, Wikstrom M, Schultz J (2002) Structure-based screening as applied to human FABP4: a highly efficient alternative to HTS for hit generation. J Am Chem Soc 124(40):11874–11880
Nakano T, Kaminuma T, Sato T, Fukuzawa K, Akiyama Y, Uebayasi M, Kitaura K (2002) Fragment molecular orbital method: use of approximate electrostatic potential. Chem Phys Lett 351(5–6):475–480
Hitaoka S, Harada M, Yoshida T, Chuman H (2010) Correlation analyses on binding affinity of sialic acid analogues with influenza virus neuraminidase-1 using ab initio MO calculations on their complex structures. J Chem Inf Model 50(10):1796–1805
Watanabe C, Fukuzawa K, Okiyama Y, Tsukamoto T, Kato A, Tanaka S, Mochizuki Y, Nakano T (2013) Three- and four-body corrected fragment molecular orbital calculations with a novel subdividing fragmentation method applicable to structure-based drug design. J Mol Graph Model 41:31–42
Wataru M, Masayuki S, Chieko E, Munetaka T, Tomomi Y, Sen T (2014) Indole derivative or salt thereof. Patent number WO2014003158
Tagami U, Takahashi K, Igarashi S, Ejima C, Yoshida T, Takeshita S, Miyanaga W, Sugiki M, Tokumasu M, Hatanaka T, Kashiwagi T, Ishikawa K, Miyano H, Mizukoshi T (2016) Interaction analysis of FABP4 inhibitors by X-ray crystallography and fragment molecular orbital analysis. ACS Med Chem Lett 7(4):435–439
Feyereisen M, Fitzgerald G, Komornicki A (1993) Use of approximate integrals in ab initio theory. An application in MP2 energy calculations. Chem Phys Lett 208 5–6:359–363
Mochizuki Y, Nakano T, Koikegami S, Tanimori S, Abe Y, Nagashima U, Kitaura K (2004) A parallelized integral-direct second-order Moller-Plesset perturbation theory method with a fragment molecular orbital scheme. Theoret Chem Acc 112(5–6):442–452
Mochizuki Y, Koikegami S, Nakano T, Amari S, Kitaura K (2004) Large scale MP2 calculations with fragment molecular orbital scheme. Chem Phys Lett 396(4–6):473–479
Fedorov DG, Kitaura K (2004) Second order Moller-Plesset perturbation theory based upon the fragment molecular orbital method. J Chem Phys 121(6):2483–2490
Wang Y, Lin HQ, Law WK, Liang WC, Zhang JF, Hu JS, Ip TM, Waye MM, Wan DC (2015) Pimozide, a novel fatty acid binding protein 4 inhibitor, promotes adipogenesis of 3T3-L1 cells by activating PPARgamma. ACS Chem Neurosci 6(2):211–218
Pierce AC, Sandretto KL, Bemis GW (2002) Kinase inhibitors and the case for CH...O hydrogen bonds in protein-ligand binding. Proteins 49(4):567–576
Acknowledgments
The authors would like to thank EA Pharma Co., Ltd., Ajinomoto Co., Inc., and Photon Factory. They also thank Leo Holroyd, Ph.D., from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2021 Springer Nature Singapore Pte Ltd.
About this chapter
Cite this chapter
Tagami, U., Takahashi, K. (2021). Cooperative Study Combining X-ray Crystal Structure Analysis and FMO Calculation: Interaction Analysis of FABP4 Inhibitors. In: Mochizuki, Y., Tanaka, S., Fukuzawa, K. (eds) Recent Advances of the Fragment Molecular Orbital Method. Springer, Singapore. https://doi.org/10.1007/978-981-15-9235-5_12
Download citation
DOI: https://doi.org/10.1007/978-981-15-9235-5_12
Published:
Publisher Name: Springer, Singapore
Print ISBN: 978-981-15-9234-8
Online ISBN: 978-981-15-9235-5
eBook Packages: Chemistry and Materials ScienceChemistry and Material Science (R0)