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A structure-based design approach to the development of novel, reversible AChE inhibitors.

Doucet-Personeni C, Bentley PD, Fletcher RJ, Kinkaid A, Kryger G, Pirard B, Taylor A, Taylor R, Taylor J, Viner R, Silman I, Sussman JL, Greenblatt HM, Lewis T
J Med Chem 44 3203-15 (2001)
Cited: 31 times
EuropePMC logo PMID: 11563919

Abstract

Chimeras of tacrine and m-(N,N,N-Trimethylammonio)trifluoroacetophenone (1) were designed as novel, reversible inhibitors of acetylcholinesterase. On the basis of the X-ray structure of the apoenzyme, a molecular modeling study determined the favored attachment positions on the 4-aminoquinoline ring (position 3 and the 4-amino nitrogen) and the favored lengths of a polymethylene link between the two moieties (respectively 5-6 and 4-5 sp(3) atoms). Seven compounds matching these criteria were synthesized, and their inhibitory potencies were determined to be in the low nanomolar range. Activity data for close analogues lacking some of the postulated key features showed that our predictions were correct. In addition, a subsequent crystal structure of acetylcholinesterase complexed with the most active compound 27 was in good agreement with our model. The design strategy is therefore validated and can now be developed further.

Reviews - 1hbj mentioned but not cited (1)

  1. Molecular dynamics simulations: advances and applications. Hospital A, Goñi JR, Orozco M, Gelpí JL. Adv Appl Bioinform Chem 8 37-47 (2015)

Articles - 1hbj mentioned but not cited (4)

  1. Flexibility of aromatic residues in the active-site gorge of acetylcholinesterase: X-ray versus molecular dynamics. Xu Y, Colletier JP, Weik M, Jiang H, Moult J, Silman I, Sussman JL. Biophys J 95 2500-2511 (2008)
  2. Pharmacophore-based virtual screening versus docking-based virtual screening: a benchmark comparison against eight targets. Chen Z, Li HL, Zhang QJ, Bao XG, Yu KQ, Luo XM, Zhu WL, Jiang HL. Acta Pharmacol Sin 30 1694-1708 (2009)
  3. Backdoor opening mechanism in acetylcholinesterase based on X-ray crystallography and molecular dynamics simulations. Sanson B, Colletier JP, Xu Y, Lang PT, Jiang H, Silman I, Sussman JL, Weik M. Protein Sci 20 1114-1118 (2011)
  4. Significant enhancement of docking sensitivity using implicit ligand sampling. Xu M, Lill MA. J Chem Inf Model 51 693-706 (2011)


Reviews citing this publication (7)

  1. The genesis of high-throughput structure-based drug discovery using protein crystallography. Kuhn P, Wilson K, Patch MG, Stevens RC. Curr Opin Chem Biol 6 704-710 (2002)
  2. Hybrids: a new paradigm to treat Alzheimer's disease. Singh M, Kaur M, Chadha N, Silakari O. Mol Divers 20 271-297 (2016)
  3. Molecular interactions of cholinesterases inhibitors using in silico methods: current status and future prospects. Khan MT. N Biotechnol 25 331-346 (2009)
  4. Medicinal chemistry of competitive kainate receptor antagonists. Larsen AM, Bunch L. ACS Chem Neurosci 2 60-74 (2011)
  5. Therapeutic Potential of Multifunctional Tacrine Analogues. Przybyłowska M, Kowalski S, Dzierzbicka K, Inkielewicz-Stepniak I. Curr Neuropharmacol 17 472-490 (2019)
  6. Discovery of Species-selective and Resistance-breaking Anticholinesterase Insecticides for the Malaria Mosquito. Carlier PR, Bloomquist JR, Totrov M, Li J. Curr Med Chem 24 2946-2958 (2017)
  7. Computer-Aided Drug Discovery in Plant Pathology. Shanmugam G, Jeon J. Plant Pathol J 33 529-542 (2017)

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  1. Antibacterial, anti-inflammatory, anti-cholinesterase and mutagenic effects of extracts obtained from some trees used in South African traditional medicine. Eldeen IM, Elgorashi EE, van Staden J. J Ethnopharmacol 102 457-464 (2005)
  2. The evolution of new enzyme function: lessons from xenobiotic metabolizing bacteria versus insecticide-resistant insects. Russell RJ, Scott C, Jackson CJ, Pandey R, Pandey G, Taylor MC, Coppin CW, Liu JW, Oakeshott JG. Evol Appl 4 225-248 (2011)
  3. Crystal structure of a squalene cyclase in complex with the potential anticholesteremic drug Ro48-8071. Lenhart A, Weihofen WA, Pleschke AE, Schulz GE. Chem Biol 9 639-645 (2002)
  4. The effect of various zinc binding groups on inhibition of histone deacetylases 1-11. Madsen AS, Kristensen HM, Lanz G, Olsen CA. ChemMedChem 9 614-626 (2014)
  5. Alaternin and emodin with hydroxyl radical inhibitory and/or scavenging activities and hepatoprotective activity on tacrine-induced cytotoxicity in HepG2 cells. Jung HA, Chung HY, Yokozawa T, Kim YC, Hyun SK, Choi JS. Arch Pharm Res 27 947-953 (2004)
  6. Molecular docking and receptor-specific 3D-QSAR studies of acetylcholinesterase inhibitors. Deb PK, Sharma A, Piplani P, Akkinepally RR. Mol Divers 16 803-823 (2012)
  7. Characterization of acetylcholinesterases, and their genes, from the hemipteran species Myzus persicae (Sulzer), Aphis gossypii (Glover), Bemisia tabaci (Gennadius) and Trialeurodes vaporariorum (Westwood). Javed N, Viner R, Williamson MS, Field LM, Devonshire AL, Moores GD. Insect Mol Biol 12 613-620 (2003)
  8. Design, synthesis and biological evaluation of bisthiazole-based trifluoromethyl ketone derivatives as potent HDAC inhibitors with improved cellular efficacy. Gong CJ, Gao AH, Zhang YM, Su MB, Chen F, Sheng L, Zhou YB, Li JY, Li J, Nan FJ. Eur J Med Chem 112 81-90 (2016)
  9. Huprines for Alzheimer's disease drug development. Muñoz-Torrero D, Camps P. Expert Opin Drug Discov 3 65-81 (2008)
  10. Conformational analysis and parallel QM/MM X-ray refinement of protein bound anti-Alzheimer drug donepezil. Fu Z, Li X, Miao Y, Merz KM. J Chem Theory Comput 9 1686-1693 (2013)
  11. Discovery of a new class of ionotropic glutamate receptor antagonists by the rational design of (2S,3R)-3-(3-carboxyphenyl)-pyrrolidine-2-carboxylic acid. Larsen AM, Venskutonytė R, Valadés EA, Nielsen B, Pickering DS, Bunch L. ACS Chem Neurosci 2 107-114 (2011)
  12. Virtual screening, molecular interaction field, molecular dynamics, docking, density functional, and ADMET properties of novel AChE inhibitors in Alzheimer's disease. da Silva CH, Carvalho I, Taft CA. J Biomol Struct Dyn 24 515-524 (2007)
  13. In silico identification and study of potential anti-mosquito juvenile hormone binding protein (MJHBP) compounds as candidates for dengue virus - Vector insecticides. Ononamadu CJ, Abdalla M, Ihegboro GO, Li J, Owolarafe TA, John TD, Tian Q. Biochem Biophys Rep 28 101178 (2021)
  14. Novel bipharmacophoric inhibitors of the cholinesterases with affinity to the muscarinic receptors M1 and M2. Messerer R, Dallanoce C, Matera C, Wehle S, Flammini L, Chirinda B, Bock A, Irmen M, Tränkle C, Barocelli E, Decker M, Sotriffer C, De Amici M, Holzgrabe U. Medchemcomm 8 1346-1359 (2017)
  15. Design, synthesis, biological evaluation, and docking study of 4-isochromanone hybrids bearing N-benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors (part II). Wang J, Wang C, Wu Z, Li X, Xu S, Liu J, Lan Q, Zhu Z, Xu J. Chem Biol Drug Des 91 756-762 (2018)
  16. Synthesis, kinetic studies and molecular modeling of novel tacrine dimers as cholinesterase inhibitors. de Aquino RA, Modolo LV, Alves RB, de Fátima Â. Org Biomol Chem 11 8395-8409 (2013)
  17. A synthesis of γ-trifluoromethyl α,β-unsaturated γ-butyrolactones using CF(3)SiMe(3) as a trifluoromethylating agent. Masusai C, Soorukram D, Kuhakarn C, Tuchinda P, Pakawatchai C, Saithong S, Reutrakul V, Pohmakotr M. Org Biomol Chem 11 6650-6658 (2013)
  18. Inactivation of acetylcholinesterase by various fluorophores. Guo L, Suarez AI, Thompson CM. J Enzyme Inhib Med Chem 25 116-120 (2010)
  19. Medicinal studies of dimeric phenols with multiple quaternary-ammonium pendant arms. Tian T, Weng XC, Song Y, Zhang LX, Zhou X, Wang Y. Chem Biodivers 4 947-954 (2007)


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