Skip to main content
SpringerLink
Log in

Molecular interactions of c-ABL mutants in complex with imatinib/nilotinib: a computational study using linear interaction energy (LIE) calculations

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

Abstract

In spite of the effectiveness of Imatinib for chronic myeloid leukemia (CML) treatment, resistance has repeatedly been reported and is associated with point mutations in the BCR-ABL chimeric gene. To overcome this resistance, several inhibitors of BCR-ABL tyrosine kinase activity were developed. In this context, computational simulations have become a powerful tool for understanding drug-protein interactions. Herein, we report a comparative molecular dynamics analysis of the interaction between two tyrosine kinase inhibitors (imatinib or nilotinib) against wild type c-ABL protein and 12 mutants, using the semi-empirical linear interaction energy (LIE) method, to assess the feasibility of this approach for studying resistance against the inhibitory activity of these drugs. In addition, to understand the structural changes that are associated with resistance, we describe the behavior of water molecules that interact simultaneously with specific residues (Glu286, Lys271 and Asp381) of c-ABL (wild type or mutant) and their relationship with drug resistance. Experimental IC50 values for the interaction between imatinib, wild type c-ABL, and 12 mutants were used to obtain the proper LIE coefficients (α, β and γ) to estimate the free energy of the binding of imatinib with wild-type and mutant proteins, and values were extrapolated for the analysis of the nilotinib/c-ABL interaction. Our results indicate that LIE was suitable to predict the superior inhibitory activity of nilotinib and the resistance to inhibition that was observed in c-ABL mutants. Additionally, for c-ABL mutants, the observed number of water molecules being turned over while interacting with amino acids Glu286, Lys271 and Asp381 was associated with resistance to imatinib, resulting in a less effective inhibition of the kinase activity.

Herein we report a comparative molecular dynamics analysis of the interaction between two Tyrosine kinase inhibitors (imatinib or nilotinib) against wild type c-ABL protein and 12 mutants, using the semi-empirical linear interaction energy (LIE) method, to assess the feasibility of this approach to study resistance against the inhibitory activity of these drugs. Our results indicate that LIE was suitable to predict the superior inhibitory activity of nilotinib, and the resistance to inhibition observed in c-ABL mutants. Additionally, to understand the structural changes associated with resistance, we described the behavior of water molecules that interact simultaneously with specific residues (Glu286, Lys271 and Asp381) of c-ABL (wild type or mutant) and their relationship with the drug conflict. ΔG values were estimated according to the linear interaction energy methodology.

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

Similar content being viewed by others

References

  1. Pear WS, Miller JP, Xu LW, Pui JC, Soffer B, Quackenbush RC, Pendergast AM, Bronson R, Aster JC, Scott ML, Baltimore D (1998) Efficient and rapid induction of a chronic myelogenous leukemia-like myeloproliferative disease in mice receiving P210 bcr/abl-transduced bone marrow. Blood 92:3780–3792

    CAS  Google Scholar 

  2. Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J, Lydon NB (1996) Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 2:561–566

    Article  CAS  Google Scholar 

  3. Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J (2000) Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase. Science 289:1938–1942

    Article  CAS  Google Scholar 

  4. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL (2001) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344:1031–1037

    Article  CAS  Google Scholar 

  5. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, Sawyers CL (2001) Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293:876–880

    Article  CAS  Google Scholar 

  6. Branford S, Rudzki Z, Walsh S, Grigg A, Arthur C, Taylor K, Herrmann R, Lynch KP, Hughes TP (2002) High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance. Blood 99:3472–3475

    Article  CAS  Google Scholar 

  7. Branford S, Rudzki Z, Walsh S, Parkinson I, Grigg A, Szer J, Taylor K, Herrmann R, Seymour JF, Arthur C, Joske D, Lynch K, Hughes T (2003) Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood 102:276–283

    Article  CAS  Google Scholar 

  8. Nicolini FE, Corm S, Le QH, Sorel N, Hayette S, Bories D, Leguay T, Roy L, Giraudier S, Tulliez M, Facon T, Mahon FX, Cayuela JM, Rousselot P, Michallet M, Preudhomme C, Guilhot F, Roche-Lestienne C (2006) Mutation status and clinical outcome of 89 imatinib mesylate-resistant chronic myelogenous leukemia patients: a retrospective analysis from the French intergroup of CML (Fi(phi)-LMC GROUP). Leukemia 20:1061–1066

    Article  CAS  Google Scholar 

  9. Manley PW, Cowan-Jacob SW, Buchdunger E, Fabbro D, Fendrich G, Furet P, Meyer T, Zimmermann J (2002) Imatinib: a selective tyrosine kinase inhibitor. Eur J Cancer 38:S19–S27

    Article  Google Scholar 

  10. Nagar B, Bornmann WG, Pellicena P, Schindler T, Veach DR, Miller WT, Clarkson B, Kuriyan J (2002) Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571). Cancer Res 62:4236–4243

    CAS  Google Scholar 

  11. Cowan-Jacob SW, Fendrich G, Floersheimer A, Furet P, Liebetanz J, Rummel G, Rheinberger P, Centeleghe M, Fabbro D, Manley PW (2007) Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia. Acta Crystallogr D 63:80–93

    Article  Google Scholar 

  12. Weisberg E, Manley PW, Cowan-Jacob SW, Hochhaus A, Griffin JD (2007) Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia. Nat Rev Cancer 7:345–356

    Article  CAS  Google Scholar 

  13. Kantarjian HM, Gattermann N, Hochhaus A, Larson R, Rafferty T, Weitzman A, Haque A, Giles F, O'Brien SG, le Coutre P (2006) A phase II study of nilotinib a novel tyrosine kinase inhibitor administered to imatinib-resistant or intolerant patients with chronic myelogenous leukemia (CML) in accelerated phase (AP). Blood 108:615a–616a

    Article  Google Scholar 

  14. le Coutre P, Bhalla K, Giles F, Baccarani M, Ossenkoppele GJ, Hochhaus A, Gattermann N, Rafferty T, Haque A, Weitzman A, Kantarjian H (2006) A phase II study of nilotinib, a novel tyrosine kinase inhibitor administered to imatinib-resistant and -intolerant patients with chronic myelogenous leukemia (CML) in chronic phase (CP). Blood 108:53a–53a

    Google Scholar 

  15. Cortes J, Kantarjian HM, Baccarani M, Brummendorf TH, Liu DL, Ossenkoppele G, Volkert ADG, Hewes B, Moore L, Zacharchuk C, Gambacorti C (2006) A phase 1/2 study of SKI-606, a dual inhibitor of src and abl kinases, in adult patients with Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) relapsed, refractory or intolerant of imatinib. Blood 108:54a–54a

    Google Scholar 

  16. Cortes J, Kim DW, Guilhot F, Rosti G, Silver RT, Gollerkeri A, Agarwal P, Branford S, Apperley JF (2006) Dasatinib (SPRYCEL (R)) in patients (pts) with chronic myelogenous leukemia in accelerated phase (AP-CML) that is imatinib-resistant (im-r) or -intolerant (im-i): updated results of the CA180-005 ‘START-A’ phase II study. Blood 108:613a–613a

    Google Scholar 

  17. Cortes JE, Kim DW, Rosti G, Rousselot P, Bleickardt E, Zink R, Sawyers C (2006) Dasatinib (D) in patients (pts) with chronic myelogenous leukemia (CML) in myeloid blast crisis (MBC) who are imatinib-resistant (IM-R) or IM-intolerant (IM-I): results of the CA180006 ‘START-B’ study. J Clin Oncol 24:344s–344s

    Article  Google Scholar 

  18. Golas JM, Arndt K, Etienne C, Lucas J, Nardin D, Gibbons J, Frost P, Ye F, Boschelli DH, Boschelli F (2003) SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice. Cancer Res 63:375–381

    CAS  Google Scholar 

  19. Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R, Cortes J, O'Brien S, Nicaise C, Bleickardt E, Blackwood-Chirchir MA, Iyer V, Chen TT, Huang F, Decillis AP, Sawyers CL (2006) Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 354:2531–2541

    Article  CAS  Google Scholar 

  20. Giles F, Cortes J, Bergstrom DA, Xiao A, Bristow P, Jones D, Verstovsek S, Thomas D, Kantarjian H, Freedman SJ (2006) MK-0457, a novel aurora kinase and BCR-ABL inhibitor, is active against BCR-ABL T315I mutant chronic myelogenous leukemia (CML). Blood 108:52a–52a

    Article  Google Scholar 

  21. Ray A, Cowan-Jacob SW, Manley PW, Mestan J, Griffin JD (2007) Identification of BCR-ABL point mutations conferring resistance to the Abl kinase inhibitor AMN107 (nilotinib) by a random mutagenesis study. Blood 109:5011–5015

    Article  CAS  Google Scholar 

  22. Weisberg E, Manley P, Mestan J, Cowan-Jacob S, Ray A, Griffin JD (2006) AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL Brit J. Cancer 94:1765–1769

    Article  CAS  Google Scholar 

  23. Pricl S, Fermeglia M, Ferrone M, Tamborini E (2005) T315l-mutated Bcr-Abl in chronic myeloid leukemia and imatinib: insights from a computational study. Mol Cancer Ther 4:1167–1174

    Article  CAS  Google Scholar 

  24. Aleksandrov A, Simonson T (2010) A molecular mechanics model for imatinib and imatinib:kinase binding. J Comput Chem 31:1550–1560

    CAS  Google Scholar 

  25. Aleksandrov A, Simonson T (2010) Molecular dynamics simulations show that conformational selection governs the binding preferences of imatinib for several tyrosine kinases. J Biol Chem 285:13807–13815

    Article  CAS  Google Scholar 

  26. Åqvist J, Medina C, Samuelsson JE (1994) A new method for predicting binding affinity in computer-aided drug design. Protein Eng 7:385–391

    Article  Google Scholar 

  27. Knight JDR, Hamelberg D, McCammon JA, Kothary R (2009) The role of conserved water molecules in the catalytic domain of protein kinases. Proteins 76:527–535

    Article  CAS  Google Scholar 

  28. Shaltiel S, Cox S, Taylor SS (1998) Conserved water molecules contribute to the extensive network of interactions at the active site of protein kinase A. Proc Natl Acad Sci USA 95:484–491

    Article  CAS  Google Scholar 

  29. Loris R, Langhorst U, De Vos S, Decanniere K, Bouckaert J, Maes D, Transue TR, Steyaert J (1999) Conserved water molecules in a large family of microbial ribonucleases. Proteins 36(1):117–134

    Article  CAS  Google Scholar 

  30. Beria I, Ballinari D, Bertrand JA, Borghi D, Bossi RT, Brasca MG, Cappella P, Caruso M, Ceccarelli W, Ciavolella A, Cristiani C, Croci V, De Ponti A, Fachin G, Ferguson RD, Lansen J, Moll JK, Pesenti E, Posteri H, Perego R, Rocchetti M, Storici P, Volpi D, Valsasina B (2010) Identification of 4,5-Dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as a new class of orally and selective polo-like kinase 1 inhibitors. J Med Chem 53:3532–3551

    Article  CAS  Google Scholar 

  31. Szep S, Park S, Boder ET, Van Duyne GD, Saven JG (2009) Structural coupling between FKBP12 and buried water. Proteins 74:603–611

    Article  CAS  Google Scholar 

  32. Rodriguez-Almazan C, Arreola R, Rodríguez-Larrea D, Aguirre-López B, Gómez-Puyou MT, Perez-Montfort R, Costas M, Gomez-Puyou A, Torres-Larios A (2008) Structural basis of human triosephosphate isomerase deficiency: mutation E104D is related to alterations of a conserved water network at the dimer interface. J Biol Chem 283:23254–23263

    Article  CAS  Google Scholar 

  33. Shan YB, Seeliger MA, Eastwood MP, Frank F, Xu HF, Jensen MO, Dror RO, Kuriyan J, Shaw DE (2009) A conserved protonation-dependent switch controls drug binding in the Abl kinase. Proc Natl Acad Sci USA 106:139–144

    Article  CAS  Google Scholar 

  34. Brandsdal BO, Österberg F, Almlöf M, Feierberg I, Luzhkov VB, Åqvist J (2003) Free energy calculations and ligand binding. Adv Protein Chem 66:123–158

    Article  CAS  Google Scholar 

  35. Singh N, Warshel A (2010) Absolute binding free energy calculations: on the accuracy of computational scoring of protein-ligand interactions. Proteins 78:1705–1723

    CAS  Google Scholar 

  36. Nagar B, Hantschel O, Young MA, Scheffzek K, Veach D, Bornmann V, Clarkson B, Superti-Furga G, Kuriyan J (2003) Structural basis for the autoinhibition of c-Abl tyrosine kinase. Cell 112:859–871

    Article  CAS  Google Scholar 

  37. Guex N, Peitsch MC (1997) SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis 18:2714–2723

    Article  CAS  Google Scholar 

  38. Weisberg E, Manley PW, Breitenstein W, Bruggen J, Cowan-Jacob SW, Ray A, Huntly B, Fabbro D, Fendrich G, Hall-Meyers E, Kung AL, Mestan J, Daley GQ, Callahan L, Catley L, Cavazza C, Mohammed A, Neuberg D, Wright RD, Gilliland DG, Griffin JD (2005) Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 7:129–141

    Article  CAS  Google Scholar 

  39. Marelius J, Kolmodin K, Feierberg I, Åqvist J (1998) Q: a molecular dynamics program for free energy calculations and empirical valence bond simulations in biomolecular systems. J Mol Graph Model 16:213–225

    Google Scholar 

  40. Daura X, Mark AE, van Gunsteren WF (1998) Parameterization of aliphatic CHn united atoms of GROMOS96 force field. J Comput Chem 19:535–547

    Article  CAS  Google Scholar 

  41. Schüttelkopf AW, van Aalten DMF (2004) PRODRG - a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr D60:1355–1363

    Google Scholar 

  42. Halgren TA (1996) Merck molecular force field 2. MMFF94 van der Waals and electrostatic parameters for intermolecular interactions. J Comput Chem 17:520–552

    Article  CAS  Google Scholar 

  43. Berendsen HJC, Postma JPM, van Gunsteren WF, Hermans J (1981) In: Pullman B, Pullman A (eds) Intermolecular forces. Springer, Heidelberg, p 584

  44. Lee FS, Warshel A (1992) A local reaction field method for fast evaluation of long-range electrostatic interactions in molecular simulations. J Chem Phys 97:3100–3107

    Article  CAS  Google Scholar 

  45. Berendsen H, Postma J, Van Gunsteren W, Dinola A, Haak J (1984) Molecular dynamics with coupling to an external bath. J Chem Phys 81:3684–3690

    Article  CAS  Google Scholar 

  46. Ryckaert JP, Ciccotti G, Berendsen HJC (1977) Numerical-integration of cartesian equations of motion of a system with constraints - molecular-dynamics of N-alkanes. J Comput Phys 23:327–341

    Article  CAS  Google Scholar 

  47. Allen MP, Tildesley DJ (1987) Computer simulation of liquids. Clarendon Press, Oxford University Press, New York, p 385

    Google Scholar 

  48. Hansson T, Marelius J, Åqvist J (1998) Ligand binding affinity prediction by linear interaction energy methods. J Comput Aided Mol Des 12:27–35

    Article  CAS  Google Scholar 

  49. Azam M, Latek RR, Daley GQ (2003) Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL. Cell 112:831–843

    Article  CAS  Google Scholar 

  50. Lee TS, Potts SJ, Kantarjian H, Cortes J, Giles F, Albitar M (2008) Molecular basis explanation for imatinib resistance of BCR-ABL due to T3151 and P-loop mutations from molecular dynamics simulations. Cancer 112:1744–1753

    Article  CAS  Google Scholar 

  51. Almlof M, Aqvist J, Smalas AO, Brandsdal BO (2006) Probing the effect of point mutations at protein-protein interfaces with free energy calculations. Biophys J 90:433–442

    Article  Google Scholar 

  52. Kyte J, Doolittle RF (1982) A simple method for displaying the hydropathic character of a protein. J Mol Biol 157:105–132

    Article  CAS  Google Scholar 

  53. O'Hare T, Eide CA, Deininger MWN (2007) Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Blood 110:2242–2249

    Article  Google Scholar 

  54. Redaelli S, Piazza R, Rostagno R, Magistroni V, Perini P, Marega M, Gambacorti-Passerini C, Boschelli F (2009) Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants. J Clin Oncol 27:469–471

    Article  CAS  Google Scholar 

Download references

Acknowledgments

Swiss-Bridge Foundation, Conselho Nacional de Desenvolvimento Científico e Tecnológico CNPq (304403/2008-3, 473914/2008-5), Convênio Instituto Nacional de Câncer – Fundação Oswaldo Cruz (INCA-FIOCRUZ), Ministry of Health, Pesquisa para o Sistema Único de Saúde - Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (PP-SUS-FAPERJ and Programa de Computação Científica (PROCC) da Fundação Oswaldo Cruz (FIOCRUZ) supported this work. The authors want to thank Dr. Héctor Seuanez Abreu for manuscript review.

Author information

Authors and Affiliations

  1. Laboratório Nacional de Computação Científica, LNCC, Av. Getúlio Vargas, 333, Petrópolis, RJ, Brazil, 25651-075

    Elen Gomes Pereira

  2. Genetics Division, Instituto Nacional de Câncer, INCA, André Cavalcanti 37, Rio de Janeiro, RJ, Brazil, 20231-050

    Miguel Ângelo Martins Moreira

  3. Programa de Computação Científica, Fundação Oswaldo Cruz, Av. Brasil 4365. Manguinhos, Rio de Janeiro, RJ, Brazil, 21040-360

    Ernesto Raúl Caffarena

Authors
  1. Elen Gomes Pereira
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Miguel Ângelo Martins Moreira
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ernesto Raúl Caffarena
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ernesto Raúl Caffarena.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pereira, E.G., Moreira, M.Â.M. & Caffarena, E.R. Molecular interactions of c-ABL mutants in complex with imatinib/nilotinib: a computational study using linear interaction energy (LIE) calculations. J Mol Model 18, 4333–4341 (2012). https://doi.org/10.1007/s00894-012-1436-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00894-012-1436-x

Keywords

Search

Navigation