Skip to main content

Advertisement

SpringerLink
Log in

Molecular docking study of the binding of aminopyridines within the K+ channel

  • Original Paper
  • Published:
Journal of Molecular Modeling Aims and scope Submit manuscript

Abstract

We present a molecular docking study aimed to identify the binding site of protonated aminopyridines for the blocking of voltage dependent K+ channels. Several active aminopyridines are considered: 2-aminopyridine, 3-aminopyridine, 4-aminopyridine, 3,4-diaminopyridine, and 4-aminoquinoleine. We apply the AutoDock force field with a lamarckian genetic algorithm, using atomic charges for the ligands derived from the electrostatic potential obtained at the B3LYP/cc-pVDZ level. We find a zone in the α-subunit of the K+ channel bearing common binding sites. This zone corresponds to five amino acids comprised between residuals Thr107 and Ala111, in the KcsA K+ channel (1J95 pdb structure). The 2-aminopyridine, 3-aminopyridine, 4-aminopyridine, and 3,4-diaminopyridine bind to the carboxylic oxygens of Thr107 and Ala111. In all cases aminopyridines are perpendicular to the axis of the pore. 4-aminoquinoleine binds to the carboxylic oxygen of Ala111. Due to its large size, the molecular plane is parallel to the axis of the pore. The charge distributions and the structures of the binding complexes suggest that the interaction is driven by formation of several hydrogen bonds. We find 2-aminopyridine, 3-aminopyridine, 4-aminopyridine, and 3,4-diaminopyridine with similar binding energy. Considering the standard error of the estimate of the AutoDock force field, this energy should lie, as a rough estimation, in the interval 3–7 kcal mol−1. On the other hand, 4-aminoquinoleine seems to have a smaller binding energy.

Three-dimensional structure of the complex between 4-AQH+ and the binding sites of the K+ pore. Only the amino acid sequence from Thr107 to Ala111 is considered. Two different representations are included. In the left, the Thr107 position is marked. The right representation shows the CO oxygens of the peptide bond as spacefilled structures.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Kirsch GE, Narahashi T (1978) Biophys J 22:507–512

    Article  CAS  Google Scholar 

  2. Molgó J, Lemeignan M, Peradejordi F, Lechat P (1985) J Pharmacol (Paris) 16(Suppl. II):109–144

    Google Scholar 

  3. Carlssom C, Rosen I, Nilsson E (1993) Acta Anaesth Scand 27:87–90

    Google Scholar 

  4. McEvoy KM, Windebank AJ, Daube NJR, Low PA (1989) N Engl J Med 321:1567–1571

    Article  CAS  Google Scholar 

  5. Schwid SR, Petrie MD, McDermott MP, Tierney DD, Manson DH, Goodman AD (1997) Neurology 48:817–821

    CAS  Google Scholar 

  6. Segal JL, Brunnemann BS (1997) Pharmacotherapy 17:415–423

    CAS  Google Scholar 

  7. Sellin LC (1981) Med Biol 59:11–20

    CAS  Google Scholar 

  8. Davidson M, Zemishlany HJ, Mohs RC, Horvath TB, Powchik P, Blass JP, Davis KL (1988) Biol Psychiat 23:485–490

    Article  CAS  Google Scholar 

  9. Wickelgren I (2002) Science 297:178–181

    Article  CAS  Google Scholar 

  10. Hayes KC, Potter PJ, Hsieh JT, Katz MA, Blight AR, Cohen R (2004) Arch Phys Med Rehab 85:29–34

    Article  Google Scholar 

  11. Smith DT, Shi R, Borgens RB, McBride JM, Jackson K, Byrn SR (2005) Eur J Med Chem 40:908–917

    Article  CAS  Google Scholar 

  12. Gillespie JI, Hutter OF (1975) J Physiol (Lond) 252:70P–71P

    CAS  Google Scholar 

  13. Molgó J, Lundh H, Thesleff S (1980) Eur J Pharmacol 61:25–34

    Article  Google Scholar 

  14. Kirsch GE, Narahashi T (1983) J Pharmacol Exp Ther 226:174–179

    CAS  Google Scholar 

  15. Howe JR, Ritchie JM (1991) J Physiol 433:183–205

    CAS  Google Scholar 

  16. Choquet D, Korn H (1992) J Gen Physiol 99:217–240

    Article  CAS  Google Scholar 

  17. Peradejordi F, Molgó J, Lemeignan M (1985) Eur J Med Chem 20:155–161

    CAS  Google Scholar 

  18. Niño A, Muñoz-Caro C (2001) Biophys Chem 91:49–60

    Article  Google Scholar 

  19. Niño A, Muñoz-Caro C, Carbó-Dorca R, Girones X (2003) Biophys Chem 104:417–427

    Article  CAS  Google Scholar 

  20. Caballero NA, Melendez FJ, Muñoz-Caro C, Niño A (2006) Biophys Chem 124:155–160

    Article  CAS  Google Scholar 

  21. Doyle DA, Cabral JM, Pfuetzner RA, Kuo A, Gulbis JM, Cohen SL, Chait BT, MacKinnon R (1998) Science 280:69–77

    Article  CAS  Google Scholar 

  22. Gulbis JM, Zhou M, Mann S, McKinnon R (2000) Science 289:123–127

    Article  CAS  Google Scholar 

  23. Zhou M, Morais-Cabral JH, Mann S, McKinnon R (2001) Nature 411:657–661

    Article  CAS  Google Scholar 

  24. Muñoz-Caro C, Niño A (2002) Biophys Chem 96:1–14

    Google Scholar 

  25. Brooijmans N, Kuntz ID (2003) Biomol Struct 23:335–373

    Article  CAS  Google Scholar 

  26. Halperin I, Ma B, Wolfson H, Nussinov R (2002) Proteins 47:409–443

    Article  CAS  Google Scholar 

  27. Krovat EM, Steindl T, Langer T (2005) Curr Comput-Aided Drug Des 1:93–102

    Article  CAS  Google Scholar 

  28. Bursulaya BD, Totrov M, Abagyan R, Brooks III CL (2003) J Comput-Aided Mol Des 17:755–763

    Article  CAS  Google Scholar 

  29. Goodsell DS, Olson AJ (1990) Proteins 8:195–202

    Article  CAS  Google Scholar 

  30. Morris GM, Goodsell DS, Huey R, Olson AJ (1996) J Comput-Aided Mol Des 10:293–304

    Article  CAS  Google Scholar 

  31. Holland JH (1975) Adaptation in natural and artificial systems. University of Michigan Press, Ann Arbor, MI

    Google Scholar 

  32. MacKinnon R, Cohen SL, Kuo A, Lee A, Chait BT (1998) Science 280:106–109

    Article  CAS  Google Scholar 

  33. Doyle DA, Cabral JM, Pfuetzner RA, Kuo A, Gulbis JM, Cohen SL, Chait BT, MacKinnon R (1998) Science 280:69–77

    Article  CAS  Google Scholar 

  34. Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (1998) J Comput Chem 19:1639–1662

    Article  CAS  Google Scholar 

  35. Hart WE (1994) Adaptive global optimization with local search. Ph.D. Thesis Computer Science and Engineering Department, University of California San Diego. See also: “ftp://ftp.cs.sandia.gov/pub/papers/wehart/thesis.ps.gz”

  36. Singh VC, Kollman PA (1984) J Comput Chem 5:129–145

    Article  CAS  Google Scholar 

  37. Besler BH, Merz KM, Kollman PA (1990) J Comput Chem 11:431–439

    Article  CAS  Google Scholar 

  38. Jensen F (1999) Introduction to computational chemistry. Wiley

  39. Laio A, Gervasio FL, VandeVondele J, Sulpizi M, Rothlisberger U (2004) J Phys Chem B 108:7963–7968

    Article  CAS  Google Scholar 

  40. Gross KC, Seybold PG, Hadad CM (2002) Int J Quantum Chem 90:445–458

    Article  CAS  Google Scholar 

  41. Gaussian 03 (2004) Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Montgomery Jr JA, Vreven T, Kudin KN, Burant JC, Millam JM, Iyengar SS, Tomasi J, Barone V, Mennucci B, Cossi M, Scalmani G, Rega N, Petersson GA, Nakatsuji H, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Klene M, Li X, Knox JE, Hratchian HP, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Ayala PY, Morokuma K, Voth GA, Salvador P, Dannenberg JJ, Zakrzewski VG, Dapprich S, Daniels AD, Strain MC, Farkas O, Malick DK, Rabuck AD, Raghavachari K, Foresman JB, Ortiz JV, Cui Q, Baboul AG, Clifford S, Cioslowski J, Stefanov BB, Liu G, Liashenko A, Piskorz P, Komaromi I, Martin RL, Fox DJ, Keith T, Al-Laham MA, Peng CY, Nanayakkara A, Challacombe M, Gill PMW, Johnson B, Chen W, Wong MW, Gonzalez C, Pople JA, Gaussian, Inc., Wallingford CT

  42. Morris GM, Goodsell DS, Huey R, Hart WE, Halliday S, Belew R, Olson AJ (2001) AutoDock version 3.0.5. User’s guide. Available from: http://www.scripps.edu/mb/olson/doc/autodock/ad305/Using_AutoDock_305.html

Download references

Acknowledgements

The authors wish to thank the Consejería de Educación y Ciencia de la Junta de Comunidades de Castilla-La Mancha (grant # PBI05-009), the Universidad de Castilla-La Mancha, the Ministerio de Educación y Ciencia (grant # FIS2005-00293), the VIEP(BUAP)-CONACYT (grant # 31/g/NAT/05) and CONACYT (research fellowship 164001) for financial support.

Author information

Authors and Affiliations

  1. Departamento de Fisicoquímica, Facultad de Ciencias Químicas, Lab. de Química Teórica, Centro de Investigación, Benemérita Universidad Autónoma de Puebla, Edif. 139, San Claudio y 14 Sur, Ciudad Universitaria, Puebla, Puebla, 72570, Mexico

    Norma Angélica Caballero & Francisco Javier Meléndez

  2. Grupo de Química Computacional y Computación de Alto Rendimiento, E. S. Informática, Universidad de Castilla-La Mancha, Paseo de la Universidad 4, 13071, Ciudad Real, Spain

    Alfonso Niño & Camelia Muñoz-Caro

Authors
  1. Norma Angélica Caballero
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Francisco Javier Meléndez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alfonso Niño
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Camelia Muñoz-Caro
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Camelia Muñoz-Caro.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Caballero, N.A., Meléndez, F.J., Niño, A. et al. Molecular docking study of the binding of aminopyridines within the K+ channel. J Mol Model 13, 579–586 (2007). https://doi.org/10.1007/s00894-007-0184-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00894-007-0184-9

Keywords

Search

Navigation