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Identifying hQC Inhibitors of Alzheimer’s Disease by Effective Customized Pharmacophore-Based Virtual Screening, Molecular Dynamic Simulation, and Binding Free Energy Analysis

Applied Biochemistry and Biotechnology volume 187, pages 1173–1192 (2019)Cite this article

Abstract

Human glutaminyl cyclase (hQC) appeared as a promising new target with its inhibitors attracted much attention for the treatment of Alzheimer’s disease (AD) in recent years. But so far, only a few compounds have been reported as hQC inhibitors. To find novel and potent hQC inhibitors, a high-specificity ZBG (zinc-binding groups)-based pharmacophore model comprising customized ZBG feature was first generated using HipHop algorithm in Discovery Studio software for screening out hQC inhibitors from the SPECS database. After purification by docking studies and drug-like ADMET properties filters, four potential hit compounds were retrieved. Subsequently, these hit compounds were subjected to 30-ns molecular dynamic (MD) simulations to explore their binding modes at the active side of hQC. MD simulations demonstrated that these hit compounds formed a chelating interaction with the zinc ion, which was consistent with the finding that the electrostatic interaction was the major driving force for binding to hQC confirmed with MMPBSA energy decomposition. Higher binding affinities of these compounds were also verified by the binding free energy calculations comparing with the references. Thus, these identified compounds might be potential hQC candidates and could be used for further investigation.

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References

  1. Kayalvili, S. (2015). Depression is a risk factor for Alzheimer disease-review. Research Journal of Pharmacy and Technology, 8(8), 1056–1058. https://doi.org/10.5958/0974-360X.2015.00181.X.

    Article  Google Scholar 

  2. Anna, M., Andrea, M., Elena, S., Michela, R., Maria, B. L., Chiara, M., & Vincenzo, T. (2013). Multifunctional tacrine derivatives in Alzheimer’s disease. Current Topics in Medicinal Chemistry, 13(15), 1771–1786. https://doi.org/10.2174/15680266113139990136.

    CAS  Article  Google Scholar 

  3. Yang, Y. H., Chen, C. H., Chou, M. C., Li, C. H., Liu, C. K., & Chen, S. H. (2013). Concentration of donepezil to the cognitive response in Alzheimer disease. Journal of Clinical Psychopharmacology, 33(3), 351–355. https://doi.org/10.1097/JCP.0b013e31828b5087.

    Article  PubMed  Google Scholar 

  4. Desai, A. K., & Grossberg, G. T. (2005). Rivastigmine for Alzheimer’s disease. Expert Review of Neurotherapeutics, 5(5), 563–580. https://doi.org/10.1586/14737175.5.5.563.

    CAS  Article  PubMed  Google Scholar 

  5. Arnold, S. E., Hyman, B. T., Flory, J., Damasio, A. R., & van Hoesen, G. W. (1991). The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer's disease. Cerebral Cortex, 1(1), 103–116. https://doi.org/10.1093/cercor/1.1.103.

    CAS  Article  PubMed  Google Scholar 

  6. Panza, F., Solfrizzi, V., Frisardi, V., Imbimbo, B. P., Capurso, C., D’Introno, A., Colacicco, A. M., Seripa, D., Vendemiale, G., Capurso, A., & Pilotto, A. (2009). Beyond the neurotransmitter-focused approach in treating Alzheimer’s disease: drugs targeting β-amyloid and tau trotein. Aging Clinical and Experimental Research, 21(6), 386–406. https://doi.org/10.1007/BF03327445.

    CAS  Article  PubMed  Google Scholar 

  7. Awadé, A. C., Cleuziat, P., GonzalèS, T., & Robert-Baudouy, J. (1994). Pyrrolidone carboxyl peptidase (Pcp): an enzyme that removes pyroglutamic acid (pGlu) from pGlu-peptides and pGlu-proteins. Proteins, 20(1), 34–51. https://doi.org/10.1002/prot.340200106.

    Article  PubMed  Google Scholar 

  8. Abraham, G. N., & Podell, D. N. (1981). Pyroglutamic acid. Non-metabolic formation, function in proteins and peptides, and characteristics of the enzymes effecting its removal. Molecular and Cellular Biochemistry, 38(1), 181–190. https://doi.org/10.1007/BF00235695.

    CAS  Article  PubMed  Google Scholar 

  9. van Coillie, E., Proost, P., van Aelst, I., Struyf, S., Polfliet, M., de Meester, I., Harvey, D. J., van Damme, J., & Opdenakker, G. (1998). Functional comparison of two human monocyte chemotactic protein-2 isoforms, role of the amino-terminal pyroglutamic acid and processing by CD26/dipeptidyl peptidase IV. Biochemistry, 37(36), 12672–12680. https://doi.org/10.1021/bi980497d.

    Article  PubMed  Google Scholar 

  10. Busby, W. H., Quackenbush, G. E., Humm, J., Youngblood, W. W., & Kizer, J. S. (1987). An enzyme(s) that converts glutaminyl-peptides into pyroglutamyl-peptides. Presence in pituitary, brain, adrenal medulla, and lymphocytes. Journal of Biological Chemistry, 262(18), 8532–8536 http://www.jbc.org/content/262/18/8532.short.

    CAS  PubMed  Google Scholar 

  11. Harigaya, Y., Saido, T. C., Eckman, C. B., Prada, C. M., Shoji, M., & Younkin, S. G. (2000). Amyloid β protein starting pyroglutamate at position 3 is a major component of the amyloid deposits in the Alzheimer's disease brain. Biochemical and Biophysical Research Communications, 276(2), 422–427. https://doi.org/10.1006/bbrc.2000.3490.

    CAS  Article  PubMed  Google Scholar 

  12. Gunn, A. P., Masters, C. L., & Cherny, R. A. (2010). Pyroglutamate-Abeta: role in the natural history of Alzheimer’s disease. International Journal of Biochemistry & Cell Biology, 42(12), 1915–1918. https://doi.org/10.1016/j.biocel.2010.08.015.

    CAS  Article  Google Scholar 

  13. Jawhar, S., Wirths, O., & Bayer, T. A. (2011). Pyroglutamate-Aβ: a hatchet man in Alzheimer disease. Journal of Biological Chemistry, 286(45), 38825–38832. https://doi.org/10.1074/jbc.R111.288308.

    CAS  Article  PubMed  Google Scholar 

  14. Schilling, S., Lauber, T., Schaupp, M., Manhart, S., Scheel, E., Böhm, G., & Demuth, H. U. (2006). On the seeding and oligomerization of pGlu-amyloid peptides (in vitro). Biochemistry, 45(41), 12393–12399. https://doi.org/10.1021/bi0612667.

    CAS  Article  PubMed  Google Scholar 

  15. Schlenzig, D., Manhart, S., Cinar, Y., Kleinschmidt, M., Hause, G., Willbold, D., Funke, S. A., Schilling, S., & Demuth, H. U. (2009). Pyroglutamate formation influences solubility and amyloidogenicity of amyloid peptides. Biochemistry, 48(29), 7072–7078. https://doi.org/10.1021/bi900818a.

    CAS  Article  PubMed  Google Scholar 

  16. Nussbaum, J. M., Schilling, S., Cynis, H., Silva, A., Swanson, E., Wangsanut, T., Tayler, K., Wiltgen, B., Hatami, A., Rönicke, R., Reymann, K., Hutter-Paier, B., Alexandru, A., Jagla, W., Graubner, S., Glabe, C. G., Demuth, H. U., & Bloom, G. S. (2012). Prion-like behaviour and tau-dependent cytotoxicity of pyroglutamylated β-amyloid. Nature, 485, 651–655. https://doi.org/10.1038/nature11060.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Alexandru, A., Jagla, W., Graubner, S., Becker, A., Bäuscher, C., Kohlmann, S., Sedlmeier, R., Raber, K. A., Cynis, H., Rönicke, R., Reymann, K. G., Petrasch-Parwez, E., Hartlage-Rübsamen, M., Waniek, A., Rossner, S., Schilling, S., Osmand, A. P., Demuth, H. U., & von Hörsten, S. (2011). Selective hippocampal neurodegeneration in transgenic mice expressing small amounts of truncated Aβ is induced by pyroglutamate-Aβ formation. Journal of Neuroscience, 31(36), 12790–12801. https://doi.org/10.1523/JNEUROSCI.1794-11.2011.

    CAS  Article  PubMed  Google Scholar 

  18. Wu, G., Miller, R. A., Connolly, B., Marcus, J., Renger, J., & Savage, M. J. (2014). Pyroglutamate-modified amyloid-β protein demonstrates similar properties in an Alzheimer's disease familial mutant knock-in mouse and Alzheimer's disease brain. Neurodegenerative Diseases, 14(2), 53–66. https://doi.org/10.1159/000353634.

    CAS  Article  PubMed  Google Scholar 

  19. Kuo, Y. M., Emmerling, M. R., Woods, A. S., Cotter, R. J., & Roher, A. E. (1997). Isolation, chemical characterization, and quantitation of Aβ 3-pyroglutamyl peptide from neuritic plaques and vascular amyloid deposits. Biochemical and Biophysical Research Communications, 237(1), 188–191. https://doi.org/10.1111/j.1471-4159.2008.05471.x.

    CAS  Article  PubMed  Google Scholar 

  20. Böckers, T. M., Kreutz, M. R., & Pohl, T. (1995). Glutaminyl-cyclase expression in the bovine/porcine hypothalamus and pituitary. Journal of Neuroendocrinology, 7(6), 445–453. https://doi.org/10.1111/j.1365-2826.1995.tb00780.x.

    Article  PubMed  Google Scholar 

  21. Schilling, S., Niestroj, A. J., Rahfeld, J. U., Hoffmann, T., Wermann, M., Zunkel, K., Wasternack, C., & Demuth, H. U. (2003). Identification of human glutaminyl cyclase as a metalloenzyme. Potent inhibition by imidazole derivatives and heterocyclic chelators. Journal of Biological Chemistry, 278(50), 49773–49779. https://doi.org/10.1074/jbc.M309077200.

    CAS  Article  PubMed  Google Scholar 

  22. Soto, C., Sigurdsson, E. M., Morelli, L., Kumar, R. A., Castaño, E. M., & Frangione, B. (1998). β-sheet breaker peptides inhibit fibrillogenesis in a rat brain model of amyloidosis: implications for Alzheimer's therapy. Nature Medicine, 4, 822–826. https://doi.org/10.1038/nm0798-822.

    CAS  Article  PubMed  Google Scholar 

  23. Kanis, J. A., Melton, L. J., Christiansen, C., Johnston, C. C., & Khaltaev, N. (1994). The diagnosis of osteoporosis. Journal of Bone and Mineral Research, 9(8), 1137–1141. https://doi.org/10.1002/jbmr.5650090802.

    CAS  Article  PubMed  Google Scholar 

  24. Aletaha, D., Neogi, T., Silman, A. J., Funovits, J., Felson, D. T., Bingham III, C. O., Birnbaum, N. S., Burmester, G. R., Bykerk, V. P., Cohen, M. D., Combe, B., Costenbader, K. H., Dougados, M., Emery, P., Ferraccioli, G., Hazes, J. M. W., Hobbs, K., Huizinga, T. W. J., Kavanaugh, A., Kay, J., Kvien, T. K., Laing, T., Mease, P., Ménard, H. A., Moreland, L. W., Naden, R. L., Pincus, T., Smolen, J. S., Stanislawska-Biernat, E., Symmons, D., Tak, P. P., Upchurch, K. S., Vencovský, J., Wolfe, F., & Hawker, G. (2010). 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European league against rheumatism collaborative initiative. Arthritis and Rheumatism, 62(9), 2569–2581. https://doi.org/10.1002/art.27584.

    Article  PubMed  Google Scholar 

  25. Hodi, F. S., O'Day, S. J., McDermott, D. F., Weber, R. W., Sosman, J. A., Haanen, J. B., Gonzalez, R., Robert, C., Schadendorf, D., Hassel, J. C., Akerley, W., van den Eertwegh, A. J. M., Lutzky, J., Lorigan, P., Vaubel, J. M., Linette, G. P., Hogg, D., Ottensmeier, C. H., Lebbé, C., Peschel, C., Quirt, I., Clark, J. I., Wolchok, J. D., Weber, J. S., Tian, J., Yellin, M. J., Nichol, G. M., Hoos, A., & Urba, W. J. (2010). Improved survival with ipilimumab in patients with metastatic melanoma. New England Journal of Medicine, 363, 711–723. https://doi.org/10.1056/NEJMoa1003466.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Jawhar, S., Wirths, O., Schilling, S., Graubner, S., Demuth, H. U., & Bayer, T. A. (2011). Overexpression of glutaminyl cyclase, the enzyme responsible for pyroglutamate Aβ formation, induces behavioral deficits, and glutaminyl cyclase knock-out rescues the behavioral phenotype in 5XFAD mice. Journal of Biological Chemistry, 286(6), 4454–4460. https://doi.org/10.1074/jbc.M110.185819.

    CAS  Article  PubMed  Google Scholar 

  27. Morawski, M., Hartlage-Rübsamen, M., Jäger, C., Waniek, A., Schilling, S., Schwab, C., McGeer, P. L., Arendt, T., Demuth, H., & Roßner, S. (2010). Distinct glutaminyl cyclase expression in edinger-westphal nucleus, locus coeruleus and nucleus basalis meynert contributes to pGlu-Aβ pathology in Alzheimer’s disease. Acta Neuropathologica, 120(2), 195–207. https://doi.org/10.1007/s00401-010-0685-y.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. Hartlage-Rübsamen, M., Morawski, M., Waniek, A., Jäger, C., Zeitschel, U., Koch, B., Cynis, H., Schilling, S., Schliebs, R., Demuth, H., & Roßner, S. (2011). Glutaminyl cyclase contributes to the formation of focal and diffuse pyroglutamate (pGlu)-Aβ deposits in hippocampus via distinct cellular mechanisms. Acta Neuropathologica, 121(6), 705–719. https://doi.org/10.1007/s00401-011-0806-2.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Schilling, S., Appl, T., Hoffmann, T., Cynis, H., Schulz, K., Jagla, W., Friedrich, D., Wermann, M., Buchholz, M., Heiser, U., von Hrsten, S., & Demuth, H. U. (2008). Inhibition of glutaminyl cyclase prevents pGlu-Aβ formation after intracortical/hippocampal micro-injection in vivo/in situ. Journal of Neurochemistry, 106(3), 1225–1236. https://doi.org/10.1111/j.1471-4159.2008.05471.x.

    CAS  Article  PubMed  Google Scholar 

  30. Schilling, S., Zeitschel, U., Hoffmann, T., Heiser, U., Francke, M., Kehlen, A., Holzer, M., Hutter-Paier, B., Prokesch, M., Windisch, M., Jagla, W., Schlenzig, D., Lindner, C., Rudolph, T., Reuter, G., Cynis, H., Montag, D., Demuth, H. U., & Rossner, S. (2008). Glutaminyl cyclase inhibition attenuates pyroglutamate Aβ and Alzheimer’s disease-like pathology. Nature Medicine, 14, 1106–1111. https://doi.org/10.1038/nm.1872.

    CAS  Article  PubMed  Google Scholar 

  31. Schilling, S., Hoffmann, T., Wermann, M., Heiser, U., Wasternack, C., & Demuth, H. U. (2002). Continuous spectrometric assays for glutaminyl cyclase activity. Analytical Biochemistry, 303(1), 49–56. https://doi.org/10.1006/abio.2001.5560.

    CAS  Article  PubMed  Google Scholar 

  32. Schilling, S., Hoffmann, T., Rosche, F., & Manhart, S. (2002). Heterologous expression and characterization of human glutaminyl cyclase: evidence for a disulfide bond with importance for catalytic activity. Biochemistry, 41(35), 10849–10857. https://doi.org/10.1021/bi0260381.

    CAS  Article  PubMed  Google Scholar 

  33. Ruiz Carrillo, D., Koch, B., Parthier, C., Wermann, M., Dambe, T., Buchholz, M., Ludwig, H. H., Heiser, U., Rahfeld, J. U., Stubbs, M. T., Schilling, S., & Demuth, H. U. (2011). Structures of glycosylated mammalian glutaminyl cyclases reveal conformational variability near the active center. Biochemistry, 50(28), 6280–6288. https://doi.org/10.1021/bi200249h.

    CAS  Article  PubMed  Google Scholar 

  34. Buchholz, M., Heiser, U., Schilling, S., Niestroj, A. J., Zunkel, K., & Demuth, H. U. (2006). The first potent inhibitors for human glutaminyl cyclase: synthesis and structure-activity relationship. Journal of Medicinal Chemistry, 49(2), 664–677. https://doi.org/10.1021/jm050756e.

    CAS  Article  PubMed  Google Scholar 

  35. Buchholz, M., Hamann, A., Aust, S., Brandt, W., Böhme, L., Hoffmann, T., Schilling, S., Demuth, H. U., & Heiser, U. (2009). Inhibitors for human glutaminyl cyclase by structure based design and bioisosteric replacement. Journal of Medicinal Chemistry, 52(22), 7069–7080. https://doi.org/10.1021/jm900969p.

    CAS  Article  PubMed  Google Scholar 

  36. Huang, K. F., Liaw, S. S., Huang, W. L., Chia, C. Y., Lo, Y. C., Chen, Y. L., & Wang, A. H. J. (2011). Structures of human Golgi-resident glutaminyl cyclase and its complexes with inhibitors reveal a large loop movement upon inhibitor binding. Journal of Biological Chemistry, 286(14), 12439–12449. https://doi.org/10.1074/jbc.M110.208595.

    CAS  Article  PubMed  Google Scholar 

  37. Koch, B., Kolenko, P., Buchholz, M., Ruiz Carrillo, D., Parthier, C., Wermann, M., Rahfeld, J. U., Reuter, G., Schilling, S., Stubbs, M. T., & Demuth, H. U. (2012). Crystal structures of glutaminyl cyclases (QCs) from drosophila melanogaster reveal active site conservation between insect and mammalian QCs. Biochemistry, 51(37), 7383–7392. https://doi.org/10.1021/bi300687g.

    CAS  Article  PubMed  Google Scholar 

  38. Koch, B., Buchholz, M., Wermann, M., Heiser, U., Schilling, S., & Demuth, H. U. (2012). Probing secondary glutaminyl cyclase (QC) inhibitor interactions applying an in silico-modeling/site-directed muta-genesis approach: implications for drug development. Chemical Biology & Drug Design, 80(6), 937–946. https://doi.org/10.1111/cbdd.12046.

    CAS  Article  Google Scholar 

  39. Ramsbeck, D., Buchholz, M., Koch, B., Böhme, L., Hoffmann, T., Demuth, H. U., & Heiser, U. (2013). Structure–activity relationships of benzimidazole-based glutaminyl cyclase inhibitors featuring a heteroaryl scaffold. Journal of Medicinal Chemistry, 56(17), 6613–6625. https://doi.org/10.1021/jm4001709.

    CAS  Article  PubMed  Google Scholar 

  40. Tran, P. T., Hoang, V. H., Thorat, S. A., Kim, S. E., Ann, J., Chang, Y. J., Nam, D. W., Song, H., Mook-Jung, I., Lee, J., & Lee, J. (2013). Structure-activity relationship of human glutaminyl cyclase inhibitors having an N-(5-methyl-1H-imidazol-1-yl) propyl thiourea template. Bioorganic & Medicinal Chemistry, 21(13), 3821–3830. https://doi.org/10.1016/j.bmc.2013.04.005.

    CAS  Article  Google Scholar 

  41. Heiser, U., Ramsbeck, D., Buchholz, M., & Niestroj, A. J. (2015). U.S. Patent No. 9,126,987. Washington, DC: U.S. Patent and Trademark Office.

  42. Li, M., Dong, Y., Yu, X., Zou, Y., Zheng, Y., Bu, X., Quan, J., He, Z., & Wu, H. (2016). Inhibitory effect of flavonoids on human glutaminyl cyclase. Bioorganic & Medicinal Chemistry, 24(10), 2280–2286. https://doi.org/10.1016/10.1016/j.bmc.2016.03.064.

    CAS  Article  Google Scholar 

  43. Hoang, V. H., Tran, P. T., Cui, M., Ngo, V. T., Ann, J., Park, J., Lee, J., Choi, K., Cho, H., & Kim, H. (2017). Discovery of potent human glutaminyl cyclase inhibitors as anti-Alzheimer's agents based on rational design. Journal of Medicinal Chemistry, 60(6), 2573–2590. https://doi.org/10.1021/acs.jmedchem.7b00098.

    CAS  Article  PubMed  Google Scholar 

  44. Yang, S. Y. (2010). Pharmacophore modeling and applications in drug discovery: challenges and recent advances. Drug Discovery Today, 15(11), 444–450. https://doi.org/10.1016/j.drudis.2010.03.013.

    CAS  Article  PubMed  Google Scholar 

  45. van de Waterbeemd, H., & Gifford, E. (2003). ADMET in silico modelling: towards prediction paradise. Nature Reviews Drug Discovery, 2, 192–204. https://doi.org/10.1038/nrd1032.

    Article  PubMed  Google Scholar 

  46. Irwin, J. J., & Shoichet, B. K. (2005). ZINC-a free database of commercially available compounds for virtual screening. Journal of Chemical Information and Modeling, 45(1), 177–182. https://doi.org/10.1021/ci049714+.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. Mysinger, M. M., Carchia, M., Irwin, J. J., & Shoichet, B. K. (2012). Directory of useful decoys, enhanced (DUD-E): better ligands and decoys for better benchmarking. Journal of Medicinal Chemistry, 55(14), 6582–6594. https://doi.org/10.1021/jm300687e.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Kirchmair, J., Markt, P., Distinto, S., Wolber, G., & Langer, T. (2008). Evaluation of the performance of 3D virtual screening protocols: RMSD comparisons, enrichment assessments, and decoy selection—what can we learn from earlier mistakes. Journal of Computer-Aided Molecular Design, 22(3), 213–228. https://doi.org/10.1007/s10822-007-9163-6.

    CAS  Article  PubMed  Google Scholar 

  49. Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J. (1997). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews, 23(1), 3–25. https://doi.org/10.1016/S0169-409X(96)00423-1.

    CAS  Article  Google Scholar 

  50. Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S., & Olson, A. J. (2009). Autodock4 and AutoDockTools4: automated docking with selective receptor flexiblity. Journal of Computational Chemistry, 30(16), 2785–2791. https://doi.org/10.1002/jcc.21256.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. Santos-Martins, D., Forli, S., Ramos, M. J., & Olson, A. J. (2014). AutoDock4Zn: an improved autodock force field for small-molecule docking to zinc metalloproteins. Journal of Chemical Information and Modeling, 54(8), 2371–2379. https://doi.org/10.1021/ci500209e.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. Berendsen, H. J. C., van der Spoel, D., & van Drunen, R. (1995). GROMACS: a message-passing parallel molecular dynamics implementation. Computer Physics Communications, 91(1), 43–56. https://doi.org/10.1016/0010-4655(95)00042-E.

    CAS  Article  Google Scholar 

  53. Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C., & Ferrin, T. E. (2004). UCSF chimera—a visualization system for exploratory research and analysis. Journal of Computational Chemistry, 25(13), 1605–1612. https://doi.org/10.1002/jcc.20084.

    CAS  Article  PubMed  Google Scholar 

  54. Lindorff-Larsen, K., Piana, S., Palmo, K., Maragakis, P., Klepei, J. L., Dror, R. O., & Shaw, D. E. (2010). Improved side-chain torsion potentials for the Amber ff99SB protein force field. Proteins, 78, 1950–1958. https://doi.org/10.1002/prot.22711.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. Wang, J., Wang, W., Kollman, P. A., & Case, D. A. (2006). Automatic atom type and bond type perception in molecular mechanical calculations. Journal of Molecular Graphics & Modelling, 25(2), 247–260. https://doi.org/10.1016/j.jmgm.2005.12.005.

    CAS  Article  Google Scholar 

  56. Sousa da Silva, A. W., & Vranken, W. F. (2012). ACPYPE-AnteChamber PYthon Parser interfacE. BMC Research Notes, 5, 367. https://doi.org/10.1186/1756-0500-5-367.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Cerutti, D. S., Duke, R. E., Darden, T. A., & Lybrand, T. P. (2009). Staggered mesh ewald: an extension of the smooth particle-mesh ewald method adding great versatility. Journal of Chemical Theory and Computation, 5(9), 2322–2338. https://doi.org/10.1021/ct9001015.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. Hess, B., Bekker, H., Berendsen, H. J. C., & Fraaije, G. E. M. (1997). LINCS: a linear constraint solver for molecular simulations. Journal of Computational Chemistry, 18(12), 1463–1472. https://doi.org/10.1002/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO,2-H.

    CAS  Article  Google Scholar 

  59. Kumari, R., Kumar, R., & Lynn, A. (2014). g_mmpbsa-A GROMACS tool for high-throughput MM-PBSA calculations. Journal of Chemical Information and Modeling, 54(7), 1951–1962. https://doi.org/10.1021/ci500020m.

    CAS  Article  PubMed  Google Scholar 

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Funding

This research received supports from the Science and Technology planning Project of Guangzhou (No. 2013J4100071) and the computation environment support by College of Pharmacy, SunYat-Sen University for Discovery Studio 2.5.

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  1. Department of Physical Chemistry, College of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, China

    Weicong Lin, Xiaojie Zheng, Shengfu Zhou & Wenjuan Wu

  2. Department of Cardiothoracic Surgery, Affiliated Second Hospital of Guangzhou Medical University, Guangzhou, 510260, China

    Danqing Fang

  3. School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou, 510275, China

    Kangcheng Zheng

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Lin, W., Zheng, X., Fang, D. et al. Identifying hQC Inhibitors of Alzheimer’s Disease by Effective Customized Pharmacophore-Based Virtual Screening, Molecular Dynamic Simulation, and Binding Free Energy Analysis. Appl Biochem Biotechnol 187, 1173–1192 (2019). https://doi.org/10.1007/s12010-018-2780-9

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  • Issue Date:

  • DOI: https://doi.org/10.1007/s12010-018-2780-9

Keywords

  • hQC
  • Pharmacophore
  • Molecular docking
  • ADMET
  • Molecular dynamics simulations
  • Binding free energy