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Fragment-guided approach to incorporating structural information into a CoMFA study: BACE-1 as an example

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Abstract

Alzheimer’s disease is an ultimately fatal neurodegenerative disease, and BACE-1 has become an attractive validated target for its therapy, with more than a hundred crystal structures deposited in the PDB. In the present study, we present a new methodology that integrates ligand-based methods with structural information derived from the receptor. 128 BACE-1 inhibitors recently disclosed by GlaxoSmithKline R&D were selected specifically because the crystal structures of 9 of these compounds complexed to BACE-1, as well as five closely related analogs, have been made available. A new fragment-guided approach was designed to incorporate this wealth of structural information into a CoMFA study, and the methodology was systematically compared to other popular approaches, such as docking, for generating a molecular alignment. The influence of the partial charges calculation method was also analyzed. Several consistent and predictive models are reported, including one with r 2 = 0.88, q 2 = 0.69 and r 2pred  = 0.72. The models obtained with the new methodology performed consistently better than those obtained by other methodologies, particularly in terms of external predictive power. The visual analyses of the contour maps in the context of the enzyme drew attention to a number of possible opportunities for the development of analogs with improved potency. These results suggest that 3D-QSAR studies may benefit from the additional structural information added by the presented methodology.

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References

  1. Mount C, Downton C (2006) Alzheimer disease: progress or profit? Nat Med 12:780–784

    Article  CAS  Google Scholar 

  2. Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA (2003) Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol 60:1119–1122

    Article  Google Scholar 

  3. Ernst RL, Hay JW (1994) The US economic and social costs of Alzheimer’s disease revisited. Am J Public Health 84:1261–1264

    Article  CAS  Google Scholar 

  4. Stachel SJ (2009) Progress toward the development of a viable BACE-1 inhibitor. Drug Dev Res 70:101–110

    Article  CAS  Google Scholar 

  5. Melnikova I (2007) Therapies for Alzheimer’s disease. Nat Rev Drug Discov 6:341–342

    Article  CAS  Google Scholar 

  6. Vassar R (2002) Beta-secretase (BACE) as a drug target for Alzheimer’s disease. Adv Drug Deliv Rev 54:1589–1602

    Article  CAS  Google Scholar 

  7. Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol 8:101–112

    Article  CAS  Google Scholar 

  8. Hunt CE, Turner AJ (2009) Cell biology, regulation and inhibition of beta-secretase (BACE-1). FEBS J 276:1845–1859

    Article  CAS  Google Scholar 

  9. Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256:184–185

    Article  CAS  Google Scholar 

  10. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356

    Article  CAS  Google Scholar 

  11. Hardy J (2009) The amyloid hypothesis for Alzheimer’s disease: a critical reappraisal. J Neurochem 110:1129–1134

    Article  CAS  Google Scholar 

  12. Luo Y, Bolon B, Kahn S, Bennett BD, Babu-Khan S, Denis P, Fan W, Kha H, Zhang J, Gong Y, Martin L, Louis JC, Yan Q, Richards WG, Citron M, Vassar R (2001) Mice deficient in BACE1, the Alzheimer’s beta-secretase, have normal phenotype and abolished beta-amyloid generation. Nat Neurosci 4:231–232

    Article  CAS  Google Scholar 

  13. Roberds SL, Anderson J, Basi G, Bienkowski MJ, Branstetter DG, Chen KS, Freedman SB, Frigon NL, Games D, Hu K, Johnson-Wood K, Kappenman KE, Kawabe TT, Kola I, Kuehn R, Lee M, Liu W, Motter R, Nichols NF, Power M, Robertson DW, Schenk D, Schoor M, Shopp GM, Shuck ME, Sinha S, Svensson KA, Tatsuno G, Tintrup H, Wijsman J, Wright S, McConlogue L (2001) BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer’s disease therapeutics. Hum Mol Genet 10:1317–1324

    Article  CAS  Google Scholar 

  14. Silvestri R (2009) Boom in the development of non-peptidic beta-secretase (BACE1) inhibitors for the treatment of Alzheimer’s disease. Med Res Rev 29:295–338

    Article  CAS  Google Scholar 

  15. Hong L, Koelsch G, Lin X, Wu S, Terzyan S, Ghosh AK, Zhang XC, Tang J (2000) Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor. Science 290:150–153

    Article  CAS  Google Scholar 

  16. 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) BACE-1 inhibitors part 1: identification of novel hydroxy ethylamines (HEAs). Bioorg Med Chem Lett 18:1011–1016

    Article  CAS  Google Scholar 

  17. 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) BACE-1 inhibitors part 2: identification of hydroxy ethylamines (HEAs) with reduced peptidic character. Bioorg Med Chem Lett 18:1017–1021

    Article  CAS  Google Scholar 

  18. 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) BACE-1 inhibitors part 3: identification of hydroxy ethylamines (HEAs) with nanomolar potency in cells. Bioorg Med Chem Lett 18:1022–1026

    Article  CAS  Google Scholar 

  19. Charrier N, Clarke B, Cutler L, Demont E, Dingwall C, Dunsdon R, East P, Hawkins J, Howes C, Hussain I, Jeffrey P, 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 (2008) Second generation of hydroxyethylamine BACE-1 inhibitors: optimizing potency and oral bioavailability. J Med Chem 51:3313–3317

    Article  CAS  Google Scholar 

  20. 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) Second generation of BACE-1 inhibitors. Part 1: the need for improved pharmacokinetics. Bioorg Med Chem Lett 19:3664–3668

    Article  CAS  Google Scholar 

  21. 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) Second generation of BACE-1 inhibitors part 2: optimisation of the non-prime side substituent. Bioorg Med Chem Lett 19:3669–3673

    Article  CAS  Google Scholar 

  22. 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) Second generation of BACE-1 inhibitors part 3: towards non hydroxyethylamine transition state mimetics. Bioorg Med Chem Lett 19:3674–3678

    Article  CAS  Google Scholar 

  23. Cramer RD, Patterson DE, Bunce JD (1988) Comparative molecular field analysis (Comfa) 0.1. Effect of shape on binding of steroids to carrier proteins. J Am Chem Soc 110:5959–5967

    Article  CAS  Google Scholar 

  24. The PyMOL molecular graphics system, version 1.2r3pre, Schrödinger, LLC

  25. Valadares NF, Castilho MS, Polikarpov I, Garratt RC (2007) 2D QSAR studies on thyroid hormone receptor ligands. Bioorg Med Chem 15:4609–4617

    Article  CAS  Google Scholar 

  26. Salum LB, Andricopulo AD (2010) Fragment-based QSAR strategies in drug design. Expert Opin Drug Discov 5:405–412

    Article  CAS  Google Scholar 

  27. Tropsha A, Golbraikh A (2007) Predictive QSAR modeling workflow, model applicability domains, and virtual screening. Curr Pharm Des 13:3494–3504

    Article  CAS  Google Scholar 

  28. Klebe G, Abraham U, Mietzner T (1994) Molecular similarity indices in a comparative analysis (CoMSIA) of drug molecules to correlate and predict their biological activity. J Med Chem 37:4130–4146

    Article  CAS  Google Scholar 

  29. Ortiz AR, Pisabarro MT, Gago F, Wade RC (1995) Prediction of drug binding affinities by comparative binding energy analysis. J Med Chem 38:2681–2691

    Article  CAS  Google Scholar 

  30. Kastenholz MA, Pastor M, Cruciani G, Haaksma EE, Fox T (2000) GRID/CPCA: a new computational tool to design selective ligands. J Med Chem 43:3033–3044

    Article  CAS  Google Scholar 

  31. Gohlke H, Klebe G (2002) DrugScore meets CoMFA: adaptation of fields for molecular comparison (AFMoC) or how to tailor knowledge-based pair-potentials to a particular protein. J Med Chem 45:4153–4170

    Article  CAS  Google Scholar 

  32. Sutherland JJ, O’Brien LA, Weaver DF (2004) A comparison of methods for modeling quantitative structure-activity relationships. J Med Chem 47:5541–5554

    Article  CAS  Google Scholar 

  33. Salum LB, Polikarpov I, Andricopulo AD (2008) Structure-based approach for the study of estrogen receptor binding affinity and subtype selectivity. J Chem Inf Model 48:2243–2253

    Article  CAS  Google Scholar 

  34. Valadares NF, Salum LB, Polikarpov I, Andricopulo AD, Garratt RC (2009) Role of halogen bonds in thyroid hormone receptor selectivity: pharmacophore-based 3D-QSSR studies. J Chem Inf Model 49:2606–2616

    Article  CAS  Google Scholar 

  35. Schüürmann G, Ebert RU, Chen J, Wang B, Kühne R (2008) External validation and prediction employing the predictive squared correlation coefficient test set activity mean vs training set activity mean. J Chem Inf Model 48:2140–2145

    Article  Google Scholar 

  36. Patel S, Vuillard L, Cleasby A, Murray CW, Yon J (2004) Apo and inhibitor complex structures of BACE (beta-secretase). J Mol Biol 343:407–416

    Article  CAS  Google Scholar 

  37. Hong L, Tang J (2004) Flap position of free memapsin 2 (beta-secretase), a model for flap opening in aspartic protease catalysis. Biochemistry 43:4689–4695

    Article  CAS  Google Scholar 

  38. Zhu Z, Sun ZY, Ye Y, Voigt J, Strickland C, Smith EM, Cumming J, Wang L, Wong J, Wang YS, Wyss DF, Chen X, Kuvelkar R, Kennedy ME, Favreau L, Parker E, McKittrick BA, Stamford A, Czarniecki M, Greenlee W, Hunter JC (2010) Discovery of cyclic acylguanidines as highly potent and selective beta-site amyloid cleaving enzyme (BACE) inhibitors: Part I-inhibitor design and validation. J Med Chem 53:951–965

    Article  CAS  Google Scholar 

  39. Steele TG, Hills ID, Nomland AA, de León P, Allison T, McGaughey G, Colussi D, Tugusheva K, Haugabook SJ, Espeseth AS, Zuck P, Graham SL, Stachel SJ (2009) Identification of a small molecule beta-secretase inhibitor that binds without catalytic aspartate engagement. Bioorg Med Chem Lett 19:17–20

    Article  CAS  Google Scholar 

  40. Xie A, Odde S, Prasanna S, Doerksen RJ (2009) Imidazole-containing farnesyltransferase inhibitors: 3D quantitative structure-activity relationships and molecular docking. J Comput Aided Mol Des 23:431–448

    Article  CAS  Google Scholar 

  41. Mittal RR, Harris L, McKinnon RA, Sorich MJ (2009) Partial charge calculation method affects CoMFA QSAR prediction accuracy. J Chem Inf Model 49:704–709

    Article  CAS  Google Scholar 

  42. Golbraikh A, Tropsha A (2002) Beware of q2!. J Mol Graph Model 20:269–276

    Article  CAS  Google Scholar 

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Acknowledgment

We would like to thank Dr. Emmanuel Demont for kindly and promptly clarifying diverse aspects about the data set inhibitors and crystal structures, and Dr. Richard Charles Garratt for critical reading of the manuscript. This work was supported by The State of São Paulo Research Foundation (FAPESP, grants 2008/58316-5 and 2007/07294-9).

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  1. Instituto de Física de São Carlos, Centro de Biotecnologia Molecular Estrutural, Universidade de São Paulo, Av. Trabalhador são-carlense 400, São Carlos-SP, 13560-970, Brazil

    Lívia Barros Salum & Napoleão Fonseca Valadares

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  1. Lívia Barros Salum
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  2. Napoleão Fonseca Valadares
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Correspondence to Napoleão Fonseca Valadares.

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Salum, L.B., Valadares, N.F. Fragment-guided approach to incorporating structural information into a CoMFA study: BACE-1 as an example. J Comput Aided Mol Des 24, 803–817 (2010). https://doi.org/10.1007/s10822-010-9375-z

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  • DOI: https://doi.org/10.1007/s10822-010-9375-z

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