Abstract
β-Secretase or β-site amyloid precursor protein cleaving enzyme (BACE-1) is a membrane-associated aspartyl protease that catalyzes the first step in the formation of amyloid β plaques responsible for Alzheimer’s disease (AD). β-Secretase has been considered as a striking therapeutic target for AD. Recently, several attempts have been focused on the development of inhibitors of this key protease. Among small molecules, scaffolds based on isophthalamide derivatives have been reported as potent non-peptidic BACE-1 inhibitors. In the present study, interactions of a 5-(N-methylmethan-4-ylsulfonamido) isophthalamide-based scaffold with BACE-1 active site residues have been evaluated via the functional B3LYP in association with split valence basis set using polarization functions (Def2-SVP). The complex ligand–receptor system including N1-(4-(cyclopropylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-(N-methylmethan-4-ylsulfonamido)-N3(1-phenylethyl) isophthalamide (5HA) and 18 amino acids constructing BACE-1 active site exhibited H-bonds, π–π stacking, and Van der Waals interactions associated with total binding energy of −268.34 kcal/mol at B3LYP/Def2-SVP level. The outcomes of conformational analysis postulated that the studied isophthalamide-based structure might not necessarily interact with the active site of BACE-1 in its optimum geometric conformation.
Graphical Abstract
Amino acid decomposition analysis on complex ligand–receptor system comprising N1-(4-(cyclopropylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-(N-methylmethan-4-ylsulfonamido)-N3(1 phenylethyl) isophthalamide and BACE-1 active site was performed using B3LYP method in association with split valence basis set using polarization functions (Def2-SVP).
Similar content being viewed by others
References
Block JH, Beale JM (2004) Wilson and Gisvold’s textbook of organic medicinal and pharmaceutical chemistry. Lippincott Williams and Wilkins, Philadelphia
Coburn CA, Stachel SJ, Jones KG et al (2006) BACE-1 inhibition by a series of w[CH2NH] reduced amide isosteres. Bioorg Med Chem Lett 16:3635–3638
Ghosh AK, Shin D, Downs D, Koelsch G, Lin X, Ermolieff J, Tang J (2000) Design of potent inhibitors for human brain memapsin 2 (-secretase). J Am Chem Soc 122(14):3522–3523
Ghosh AK, Kumaragurubaran N, Hong L et al (2007) Design, synthesis, and X-ray structure of potent memapsin 2 (â-secretase) inhibitors with isophthalamide derivatives as the P2–P3-ligands. J Med Chem 50:2399–2407
Hamada Y, Abdel-Rahman H, Yamani A et al (2008) BACE1 inhibitors: optimization by replacing the residue with non-acidic moiety. Bioorg Med Chem Lett 18(5):1649–1653
Hanessian S, Yun H, Hou Y, Tintelnot-Blomley M (2005) Stereoselective synthesis of constrained azacyclic hydroxyethylene isosteres as aspartic protease inhibitors: dipolar cycloaddition and related methodologies toward branched pyrrolidine and pyrrolidinone carboxylic acids. J Org Chem 70(17):6746–6756
Hevener KE, Zhao W, Ball DM, Babaoglu K, Qi J, White SW, Lee RE (2009) Validation of molecular docking programs for virtual screening against Dihydropteroate synthase. J Chem Inf Model 49(2):444–460
Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14:34–38
Kortum SW, Benson TE, Bienkowski MJ et al (2007) Potent and selective isophthalamide S2 hydroxyethylamine inhibitors of BACE1. Bioorg Med Chem Lett 17:3378–3383
Kurz A, Perneczky R (2011) Novel insights for the treatment of Alzheimer’s disease. Prog Neuro-psychopharmacol Biol Psychiatry 35(2):373–379
Levine IN (2008) Physical chemistry. McGraw-Hill, New York
Luo Y, Bolon B, Kahn S et al (2001) Mice deficient in BACE1, the Alzheimer’s b-secretase, have normal phenotype and abolished b-amyloid generation. Nat Neurosci 4:231–232
Madden J, Dod JR, Godemann R et al (2010) Fragment-based discovery and optimization of BACE1 inhibitors. Bioorg Med Chem Lett 20:5329–5333
Malamas MS, Erdei J, Gunawan I et al (2010) Design and synthesis of 5,50-disubstituted aminohydantoins as potent and selective human β-secretase (BACE1) inhibitors. J Med Chem 53:1146–1158
Manzenrieder F, Frank AO, Huber T, Dorner-Ciossek C, Kessler H (2007) Synthesis and biological evaluation of phosphino dipeptide isostere inhibitor of human [beta]-secretase (BACE1). Bioorg Med Chem 15(12):4136–4143
McGovern SL, Shoichet BK (2003) Information decay in molecular docking screens against holo, apo, and modeled conformations of enzymes. J Med Chem 46(14):2895–2907
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease. Neurology 34(7):939
Mulliken RS (1955) Electronic population analysis on LCAO MO molecular wave functions. IV. Bonding and antibonding in LCAO and valence bond theories. J Chem Phys 23:2343
Neese F (2011) ORCA—an ab initio, density functional and semiempirical program package, version 2.8.0. University of Bonn, Bonn
Probst GD, Bowers S, Sealy JM et al (2010) Design and synthesis of hydroxyethylamine (HEA) BACE-1 inhibitors: structure–activity relationship of the aryl region. Bioorg Med Chem Lett 20:6034–6039
Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362(4):329–344
Rajapakse HA, Nantermet PG, Selnick HG et al (2006) Discovery of oxadiazoyl tertiary carbinamine inhibitors of β-secretase (BACE-1). J Med Chem 49:7270–7273
Roberds SL, Anderson J, Basi G et al (2001) BACE knockout mice are healthy despite lacking the primary -secretase activity in brain: implications for Alzheimer’s disease therapeutics. Hum Mol Genet 10(12):1317–1324
Schäfer A, Horn H, Ahlrichs R (1992) Fully optimized contracted Gaussian basis sets for atoms Li to Kr. J Chem Phys 97(4):2571–2577
Selkoe DJ (2000) Toward a comprehensive theory for Alzheimer’s disease. Hypothesis: Alzheimer’s disease is caused by the cerebral accumulation and cytotoxicity of amyloid beta-protein. Ann NY Acad Sci 924:17–25
Selkoe DJ (2008) Soluble oligomers of the amyloid [beta]-protein impair synaptic plasticity and behavior. Behav Brain Res 192(1):106–113
Silvestri R (2009) Boom in the development of non-peptidic b-secretase (BACE1) inhibitors for the treatment of Alzheimer’s disease. Med Res Rev 29(2):295–338
Stachel SJ, Coburn CA, Steele TG et al (2004) Structure-based design of potent and selective cell-permeable inhibitors of human beta-secretase (BACE-1). J Med Chem 47(26):6447–6450
Stachel SJ, Coburn CA, Steele TG et al (2006) Conformationally biased P3 amide replacements of [beta]-secretase inhibitors. Bioorg Med Chem Lett 16(3):641–644
Vassar R (2002) [beta]-Secretase (BACE) as a drug target for Alzheimer’s disease. Adv Drug Deliv Rev 54(12):1589–1602
Wallace AC, Laskowski RA, Thornton JM (1995) LIGPLOT—a program to generate schematic diagrams of protein ligand interactions. Protein Eng 8:27–134
Wångsell F, Gustafsson K, Kvarnström I et al (2010) Synthesis of potent BACE-1 inhibitors incorporating a hydroxyethylene isostere as central core. Eur J Med Chem 45:870–882
Xiao K, Li X, Li J et al (2006) Design, synthesis, and evaluation of Leu* Ala hydroxyethylene-based non-peptide [beta]-secretase (BACE) inhibitors. Bioorg Med Chem 14(13):4535–4551
Xiong YZ, Chen PY (2008) ONIOM DFT/PM3 calculation on the interaction between STI-571 and abelson tyrosine kinase. J Mol Model 14(11):1083–1086
Acknowledgments
Financial supports of this Project by Research Council of Shiraz University of Medical Sciences are acknowledged.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Razzaghi-Asl, N., Ebadi, A., Edraki, N. et al. Ab initio modeling of a potent isophthalamide-based BACE-1 inhibitor: amino acid decomposition analysis. Med Chem Res 22, 3259–3269 (2013). https://doi.org/10.1007/s00044-012-0277-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00044-012-0277-6