Advertisement

Applied Biochemistry and Biotechnology

, Volume 187, Issue 4, pp 1173–1192 | Cite as

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

  • Weicong Lin
  • Xiaojie Zheng
  • Danqing Fang
  • Shengfu Zhou
  • Wenjuan WuEmail author
  • Kangcheng Zheng
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.

Keywords

hQC Pharmacophore Molecular docking ADMET Molecular dynamics simulations Binding free energy 

Notes

Funding information

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.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 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.Google Scholar
  2. 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.Google Scholar
  3. 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.Google Scholar
  4. 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.Google Scholar
  5. 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.Google Scholar
  6. 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.Google Scholar
  7. 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.Google Scholar
  8. 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.Google Scholar
  9. 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.Google Scholar
  10. 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.Google Scholar
  11. 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.Google Scholar
  12. 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.Google Scholar
  13. 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.Google Scholar
  14. 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.Google Scholar
  15. 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.Google Scholar
  16. 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.Google Scholar
  17. 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.Google Scholar
  18. 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.Google Scholar
  19. 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.Google Scholar
  20. 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.Google Scholar
  21. 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.Google Scholar
  22. 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.Google Scholar
  23. 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.Google Scholar
  24. 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.Google Scholar
  25. 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.Google Scholar
  26. 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.Google Scholar
  27. 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.Google Scholar
  28. 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.Google Scholar
  29. 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.Google Scholar
  30. 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.Google Scholar
  31. 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.Google Scholar
  32. 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.Google Scholar
  33. 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.Google Scholar
  34. 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.Google Scholar
  35. 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.Google Scholar
  36. 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.Google Scholar
  37. 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.Google Scholar
  38. 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.Google Scholar
  39. 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.Google Scholar
  40. 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.Google Scholar
  41. 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.Google Scholar
  42. 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.Google Scholar
  43. 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.Google Scholar
  44. 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.Google Scholar
  45. 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.Google Scholar
  46. 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+.Google Scholar
  47. 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.Google Scholar
  48. 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.Google Scholar
  49. 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.Google Scholar
  50. 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.Google Scholar
  51. 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.Google Scholar
  52. 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.Google Scholar
  53. 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.Google Scholar
  54. 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.Google Scholar
  55. 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.Google Scholar
  56. 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.Google Scholar
  57. 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.Google Scholar
  58. 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.Google Scholar
  59. 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.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Physical Chemistry, College of PharmacyGuangdong Pharmaceutical UniversityGuangzhouChina
  2. 2.Department of Cardiothoracic SurgeryAffiliated Second Hospital of Guangzhou Medical UniversityGuangzhouChina
  3. 3.School of Chemistry and Chemical EngineeringSun Yat-Sen UniversityGuangzhouChina

Personalised recommendations