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Quantum mechanics study of the hydroxyethylamines–BACE-1 active site interaction energies

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Abstract

The identification of BACE-1, a key enzyme in the production of Amyloid-β (Aβ) peptides, generated by the proteolytic processing of amyloid precursor protein, was a major advance in the field of Alzheimer’s disease as this pathology is characterized by the presence of extracellular senile plaques, mainly comprised of Aβ peptides. Hydroxyethylamines have demonstrated a remarkable potential, like candidate drugs, for this disease using BACE-1 as target. Density Functional Theory calculations were employed to estimate interaction energies for the complexes formed between the hydroxyethylamine derivated inhibitors and 24 residues in the BACE-1 active site. The collected data offered not only a general but a particular quantitative description that gives a deep insight of the interactions in the active site, showing at the same time how ligand structural variations affect them. Polar interactions are the major energetic contributors for complex stabilization and those ones with charged aspartate residues are highlighted, as they contribute over 90% of the total attractive interaction energy. Ligand-ARG296 residue interaction reports the most repulsive value and decreasing of the magnitude of this repulsion can be a key feature for the design of novel and more potent BACE-1 inhibitors. Also it was explained why sultam derivated BACE-1 inhibitors are better ones than lactam based. Hydrophobic interactions concentrated at S1 zone and other relevant repulsions and attractions were also evaluated. The comparison of two different theory levels (X3LYP and M062X) allowed to confirm the relevance of the detected interactions as each theory level has its own strength to depict the forces involved, as is the case of M062X which is better describing the hydrophobic interactions. Those facts were also evaluated and confirmed by comparing the quantitative trend, of selected ligand-residue interactions, with MP2 theory level as reference standard method for electrostatic plus dispersion energies.

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References

  1. Vassar R (2002) Adv Drug Deliv Rev 54:1589–1602

    Article  CAS  Google Scholar 

  2. Evin G, Weidemann A (2002) Neurobiol Aging 22:799–809

    Google Scholar 

  3. McGeer PL, McGeer EG (2001) Neurobiol Aging 22:799–809

    Article  CAS  Google Scholar 

  4. Ghosh AK, Gemma S, Tang J (2008) Neurotherapeutics 5:399–408

    Article  CAS  Google Scholar 

  5. Rodriguez-Barrios F, Gago F (2004) Curr Top Med Chem 4:991–1007

    Article  CAS  Google Scholar 

  6. Clarke B, Demont E, Dingwall C, Dunsdon R, Faller A, Hawkins J, Hussain I, MacPherson D, Maile G, Matico R, Milner P, Mosley J, Naylor A, O’Brien A, Redshaw S, Riddell D, Rowland P, Soleil V, Smith KJ, Stanway S, Stemp G, Sweitzer S, Theobald P, Vesey D, Walter DS, Ward J, Wayne G (2008) Bioorg Med Chem Lett 18:1011–1016

    Article  CAS  Google Scholar 

  7. Clarke B, Demont E, Dingwall C, Dunsdon R, Faller A, Hawkins J, Hussain I, MacPherson D, Maile G, Matico R, Milner P, Mosley J, Naylor A, O’Brien A, Redshaw S, Riddell D, Rowland P, Soleil V, Smith KJ, Stanway S, Stemp G, Sweitzer S, Theobald P, Vesey D, Walter DS, Ward J, Wayne G (2008) Bioorg Med Chem Lett 18:1017–1021

    Article  CAS  Google Scholar 

  8. Beswick P, Charrier N, Clarke B, Demont E, Dingwall C, Dunsdon R, Faller A, Gleave R, Hawkins J, Hussain I, Johnson CN, MacPherson D, Maile G, Matico R, Milner P, Mosley J, Naylor A, O’Brien A, Redshaw S, Riddell D, Rowland P, Skidmore J, Soleil V, Smith KJ, Stanway S, Stemp G, Stuart A, Sweitzer S, Theobald P, Vesey D, Walter DS, Ward J, Wayne G (2008) Bioorg Med Chem Lett 18:1022–1026

    Article  CAS  Google Scholar 

  9. Charrier N, Clarke B, Cutler L, Demont E, Dingwall C, Dunsdon R, Hawkins J, Howes C, Hubbard J, Hussain I, Maile G, Matico R, Mosley J, Naylor A, O’Brien A, Redshaw S, Rowland P, Soleil V, Smith KJ, Sweitzer S, Theobald P, Vesey D, Walter DS, Wayne G (2009) Bioorg Med Chem Lett 19:3664–3668

    Article  CAS  Google Scholar 

  10. Charrier N, Clarke B, Demont E, Dingwall C, Dunsdon R, Hawkins J, Hubbard J, Hussain I, Maile G, Matico R, Mosley J, Naylor A, O’Brien A, Redshaw S, Rowland P, Soleil V, Smith KJ, Sweitzer S, Theobald P, Vesey D, Walter DS, Wayne G (2009) Bioorg Med Chem Lett 19:3669–3673

    Article  CAS  Google Scholar 

  11. Charrier N, Clarke B, Cutler L, Demont E, Dingwall C, Dunsdon R, Hawkins J, Howes C, Hubbard J, Hussain I, Maile G, Matico R, Mosley J, Naylor A, O’Brien A, Redshaw S, Rowland P, Soleil V, Smith KJ, Sweitzer S, Theobald P, Vesey D, Walter DS, Wayne G (2009) Bioorg Med Chem Lett 19:3674–3678

    Article  CAS  Google Scholar 

  12. Truong AP, Probst GD, Aquino J, Fang L, Brogley L, Sealy JM, Hom RK, Tucker JA, Jhn V, Tung JS, Pleiss MA, Konradi AW, Sham HL, Dappen MS, Tóth G, Yao N, Brecht E, Pan H, Artis DR, Ruslim L, Bova MP, Sinha S, Yednock TA, Zmolek W, Quinn KP, Sauer JM (2010) Bioorg Med Chem Lett 20:4789–4794

    Article  CAS  Google Scholar 

  13. Gao J, Winslow SL, Vander Velde D, Aubé J, Borchardt RT (2001) J Pept Res 57:361–373

    Article  CAS  Google Scholar 

  14. Hussain I, Hawkins J, Harrison D, Hille C, Wayne G, Cutler L, Buck T, Walter D, Demont E, Howes C, Naylor A, Jeffrey P, Gonzalez MI, Dingwall C, Michel A, Redshaw S, Davis JB (2007) J Neurochem 100:802–809

    Article  CAS  Google Scholar 

  15. Salum LB, Valadares NF (2010) J Comput Aided Mol Des 24:803–817

    Article  CAS  Google Scholar 

  16. Rizzi L, Vaiana N, Sagui F, Genesio E, Pilli E, Porcari V, Romeo S (2009) Protein Pept Lett 16:86–90

    Article  CAS  Google Scholar 

  17. Manoharan P, Vijayan RSK, Ghoshal NJ (2010) Comput Aided Mol Des 24:843–864

    Article  CAS  Google Scholar 

  18. Pandey A, Mungalpara J, Mohan CG (2010) Mol Divers 14:39–49

    Article  CAS  Google Scholar 

  19. Utkov H, Livengood M, Cafiero M (2010) Annu Rep Comput Chem 10:96–112

    Article  Google Scholar 

  20. Söderhjelm P, Kongsted J, Ryde U (2010) J Chem Theor Comput 6:1726–1737

    Article  Google Scholar 

  21. Söderhjelm P, Aquilante F, Ryde U (2009) J Phys Chem B 113:11085–11094

    Article  Google Scholar 

  22. Alzate-Morales JH, Contreras R, Soriano A, Tuñon I, Silla E (2007) Biophys J 92:430–439

    Article  CAS  Google Scholar 

  23. Zhao Y, Truhlar D (2008) Theor Chem Acc 120:215–241

    Article  CAS  Google Scholar 

  24. Xu X, Goddard WA (2004) PNAS 101:2673–2677

    Article  CAS  Google Scholar 

  25. Valdes H, Pluhácková K, Pitonák M, Rezác J, Hobza P (2007) Phys Chem Chem Phys 10:2747–27578

    Article  Google Scholar 

  26. Cole SL, Vassar R (2007) Molecular Neurodegener 2:22

    Article  Google Scholar 

  27. Bernstein FC, Koetzle TF, Williams GJ, Meyer EF, Brice MD, Rodgers JR, Kennard O, Shimanouchi T, Tasumi M (1977) Eur J Biochem 80:319–324

    Article  CAS  Google Scholar 

  28. Accelrys Software Inc. (2010) DSV 3.0

  29. Ren P, Ponder JW (2003) The J Phys Chem B 107:5933–5947

    Article  CAS  Google Scholar 

  30. Chesmitry Stewart Computational (2009) MOPAC 2009 Version 10040L

  31. Klamt A, Schüümann GJ (1993) J Chem Soc Perkin Trans 25:799–805

    Google Scholar 

  32. Stewart JJ (2009) Mol Model 15:765–805

    Article  CAS  Google Scholar 

  33. Stewart JJ (2007) Mol Model 13:1173–1213

    Article  CAS  Google Scholar 

  34. Yamazaki T, Nicholson LK, Wingfield P, Stahl SJ, Kaufman JD, Eyermann CJ, Hodge CN, Lam PYS, Torchia DA (1994) J Am Chem Soc 116:10791–10792

    Article  CAS  Google Scholar 

  35. Hyland LJ, Tomaszek TA, Roberts GD, Carr SA, Magaard VW, Bryan HL, Fakhoury SA, Moore ML, Minnich MD, Culp JS (1991) Biochemistry 30:8441–8453

    Article  CAS  Google Scholar 

  36. Hyland LJ, Tomaszek TA, Meek TD (1991) Biochemistry 30:8454–8463

    Article  CAS  Google Scholar 

  37. Yu N, Hayik SA, Wang B, Liao N, Reynolds CH, Merz KM (2006) J Chem Theor Comput 2:1057–1069

    Article  CAS  Google Scholar 

  38. Polgar T, Keserü GM (2005) J Med Chem 48:3749–3755

    Article  CAS  Google Scholar 

  39. Rajamani R, Reynolds CH (2004) J Med Chem 47:5159–5166

    Article  CAS  Google Scholar 

  40. Park H, Lee S (2003) J Am Chem Soc 125:16416–16422

    Article  CAS  Google Scholar 

  41. Huang D, Caflisch A (2004) J Med Chem 47:5791–5797

    Article  CAS  Google Scholar 

  42. Diez y Riega H, Rincón L, Almeida R (2003) J Phys Org Chem 16:107–113

    Article  CAS  Google Scholar 

  43. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery JA, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam NJ, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian, Inc., Wallingford

  44. Allouche AR (2011) J Comput Chem 32:174–182

    Article  CAS  Google Scholar 

  45. Boys SF, Bernardi F (1970) Mol Phys 19:553–566

    Article  CAS  Google Scholar 

  46. Almlof J, Helgaker T, Taylor PR (1988) J Phys Chem 92:3029–3033

    Article  CAS  Google Scholar 

  47. Stigler SM (2008) Stat Sci 23:261–271

    Article  Google Scholar 

  48. Clarke B, Cutler L, Demont E, Dingwall C, Dunsdon R, Hawkins J, Howes C, Hussain I, Maile G, Matico R, Mosley J, Naylor A, O’Brien A, Redshaw S, Rowland P, Soleil V, Smith KJ, Sweitzer S, Theobald P, Vesey D, Walter DS, Wayne G (2010) Bioorg Med Chem Lett 20:4639–4644

    Article  CAS  Google Scholar 

  49. Head-Gordon M, Pople JA, Frisch MJ (1988) Chem Phys Lett 153:503–506

    Article  CAS  Google Scholar 

  50. Gu J, Wang J, Leszczynski J, Xie Y, Schaefer HF III (2008) Chem Phys Lett 459:164–166

    Article  CAS  Google Scholar 

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Acknowledgments

We want to express our gratitude to professor Abdul-Rahman Allouche for his very kind cooperation, attending our requirements for Gabedit source modification necessary for the calculations. We also acknowledge COLCIENCIAS and the Universidad of Cartagena for supporting and funding our research group. The authors greatly appreciate feedback and suggestions made by anonymous referees.

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Authors and Affiliations

  1. Grupo de Química Cuántica y Teórica, Programa de Química, Facultad de Ciencias Exactas y Naturales, Universidad de Cartagena, Cartagena, Colombia

    Carlos Gueto-Tettay, Juan Carlos Drosos & Ricardo Vivas-Reyes

  2. Grupo de Química Bioorgánica, Programa de Química, Facultad de Ciencias Exactas y Naturales, Universidad de Cartagena, Cartagena, Colombia

    Carlos Gueto-Tettay & Juan Carlos Drosos

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  1. Carlos Gueto-Tettay
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Correspondence to Ricardo Vivas-Reyes.

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Gueto-Tettay, C., Drosos, J.C. & Vivas-Reyes, R. Quantum mechanics study of the hydroxyethylamines–BACE-1 active site interaction energies. J Comput Aided Mol Des 25, 583–597 (2011). https://doi.org/10.1007/s10822-011-9443-z

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