Medicinal Chemistry Research

, Volume 23, Issue 11, pp 4657–4668 | Cite as

Computational insights into the active site of human breast cancer resistance protein (BCRP/ABCG2): a similarity search approach

  • Kanchan Khandelwal
  • Rahul Prakashchand Gangwal
  • Udghosh Singh
  • Rameshwar Prajapati
  • Mangesh V. Damre
  • Abhay T. SangamwarEmail author
Original Research


Human breast cancer resistance protein (BCRP) belongs to the G subfamily of ATP-binding cassette transporter. Over-expression of BCRP in cancer cells limits the efficacy of many chemotherapeutic agents, resulting in multiple drug resistance. A clear understanding of inhibitor-binding mode will be useful in the design of BCRP-selective inhibitor. To gain structural insights into the active site of BCRP, three-dimensional quantitative structure–activity relationship (3D-QSAR) models were developed for two different chemical series (flavonoids and chalcones derivatives) of BCRP inhibitors. Stable and statistically reliable predictive CoMFA and CoMSIA models have shown significant \(r_{\rm cv}^{2} > 0.7,\;r_{\rm ncv}^{2} > 0.9,\;r_{\rm bs}^{2} > 0.9,\;r_{\rm pred}^{2} > 0.6\) and a small standard deviation <0.2, indicating a better statistical relationship between the activity and descriptors. 3D contour maps generated from these models were analyzed individually, which provided the regions in space where interactive fields may influence the inhibitory activity of BCRP inhibitors. The similarity search between site points, generated from contour maps, and binding pockets identified using different pocket search tools, provided essential clues for characterization of the binding site. Molecular docking analysis reveals that Asp643, Asp650, and Val651 of the nucleotide-binding domain play an important role in binding of flavonoids and chalcones. The structural insights obtained from 3D-QSAR and molecular docking studies will serve as a guideline for designing and predicting novel BCRP inhibitors.


BCRP inhibitors CoMFA CoMSIA Molecular docking 3D-QSAR Site point similarity search 



The authors acknowledge financial support from the council of scientific and industrial research (CSIR), New Delhi.

Supplementary material

44_2014_1035_MOESM1_ESM.doc (1.2 mb)
Supplementary material 1 (DOC 1250 kb)


  1. Ahmed-Belkacem A, Pozza A, Munoz-Martinez F, Bates SE, Castanys S, Gamarro F, Di Pietro A, Pérez-Victoria JM (2005) Flavonoid structure-activity studies identify 6-prenylchrysin and tectochrysin as potent and specific inhibitors of breast cancer resistance protein ABCG2. Cancer Res 65(11):4852–4860CrossRefPubMedGoogle Scholar
  2. Ahmed-Belkacem A, Pozza A, Macalou S, Perez-Victoria JM, Boumendjel A, Di Pietro A (2006) Inhibitors of cancer cell multidrug resistance mediated by breast cancer resistance protein (BCRP/ABCG2). Anticancer Drugs 17(3):239–243CrossRefPubMedGoogle Scholar
  3. Allen JD, van Dort SC, Buitelaar M, van Tellingen O, Schinkel AH (2003) Mouse breast cancer resistance protein (Bcrp1/Abcg2) mediates etoposide resistance and transport, but etoposide oral availability is limited primarily by P-glycoprotein. Cancer Res 63(6):1339–1344PubMedGoogle Scholar
  4. Allikmets R, Schriml LM, Hutchinson A, Romano-Spica V, Dean M (1998) A human placenta-specific ATP-binding cassette gene (ABCP) on chromosome 4q22 that is involved in multidrug resistance. Cancer Res 58(23):5337–5339PubMedGoogle Scholar
  5. Ambure PS, Gangwal RP, Sangamwar AT (2012) 3D-QSAR and molecular docking analysis of biphenyl amide derivatives as p38α mitogen activated protein kinase inhibitors. Mol Divers 16:377–388CrossRefPubMedGoogle Scholar
  6. Boumendjel A, Macalou S, Ahmed-Belkacem A, Blanc M, Di Pietro A (2007) Acridone derivatives: design, synthesis, and inhibition of breast cancer resistance protein ABCG2. Bioorg Med Chem 15(8):2892–2897CrossRefPubMedGoogle Scholar
  7. Boumendjel A, Macalou S, Valdameri G, Pozza A, Gauthier C, Arnaud O, Nicolle E, Magnard S, Falson P, Terreux R (2011) Targeting the multidrug ABCG2 transporter with flavonoidic inhibitors: in vitro optimization and in vivo validation. Curr Med Chem 18(22):3387–3401CrossRefPubMedGoogle Scholar
  8. Colabufo NA, Berardi F, Perrone MG, Cantore M, Contino M, Inglese C, Niso M, Perrone R (2009) Multi-drug-resistance-reverting agents: 2-aryloxazole and 2-arylthiazole derivatives as potent BCRP or MRP1 inhibitors. ChemMedChem 4(2):188–195CrossRefPubMedGoogle Scholar
  9. Cooray HC, Blackmore CG, Maskell L, Barrand MA (2002) Localisation of breast cancer resistance protein in microvessel endothelium of human brain. NeuroReport 13(16):2059–2063CrossRefPubMedGoogle Scholar
  10. Doyle LA, Yang W, Abruzzo LV, Krogmann T, Gao Y, Rishi AK, Ross DD (1998) A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci USA 95(26):15665–15670PubMedCentralCrossRefPubMedGoogle Scholar
  11. Gasteiger J, Marsili M (1980) Iterative partial equalization of orbital electronegativity—a rapid access to atomic charges. Tetrahedron 36(22):3219–3228CrossRefGoogle Scholar
  12. Glavinas H, Krajcsi P, Cserepes J, Sarkadi B (2004) The role of ABC transporters in drug resistance, metabolism and toxicity. Curr Drug Deliv 1(1):27–42CrossRefPubMedGoogle Scholar
  13. Gupta P, Garg P, Roy N (2011) Comparative docking and CoMFA analysis of curcumine derivatives as HIV-1 integrase inhibitors. Mol Divers 15(3):1–18Google Scholar
  14. Hazai E, Bikádi Z (2008) Homology modeling of breast cancer resistance protein (ABCG2). J Struct Biol 162(1):63–74CrossRefPubMedGoogle Scholar
  15. Imai Y, Tsukahara S, Asada S, Sugimoto Y (2004) Phytoestrogens/flavonoids reverse breast cancer resistance protein/ABCG2-mediated multidrug resistance. Cancer Res 64(12):4346–4352CrossRefPubMedGoogle Scholar
  16. Jonker JW, Smit JW, Brinkhuis RF, Maliepaard M, Beijnen JH, Schellens JHM, Schinkel AH (2000) Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan. J Natl Cancer Inst 92(20):1651–1656CrossRefPubMedGoogle Scholar
  17. Jonker JW, Buitelaar M, Wagenaar E, Van Der Valk MA, Scheffer GL, Scheper RJ, Plösch T, Kuipers F, Elferink RPJ, Rosing H (2002) The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria. Proc Natl Acad Sci U S A 99(24):15649–15654PubMedCentralCrossRefPubMedGoogle Scholar
  18. Juvale K, Pape VFS, Wiese M (2012) Investigation of chalcones and benzochalcones as inhibitors of breast cancer resistance protein. Bioorg Med Chem 20:346–355CrossRefPubMedGoogle Scholar
  19. Kage K, Tsukahara S, Sugiyama T, Asada S, Ishikawa E, Tsuruo T, Sugimoto Y (2002) Dominant-negative inhibition of breast cancer resistance protein as drug efflux pump through the inhibition of S–S dependent homodimerization. Int J Cancer 97(5):626–630CrossRefPubMedGoogle Scholar
  20. Kanzaki A, Toi M, Nakayama K, Bando H, Mutoh M, Uchida T, Fukumoto M, Takebayashi Y (2001) Expression of multidrug resistance-related transporters in human breast carcinoma. Cancer Sci 92(4):452–458Google Scholar
  21. Katayama K, Masuyama K, Yoshioka S, Hasegawa H, Mitsuhashi J, Sugimoto Y (2007) Flavonoids inhibit breast cancer resistance protein-mediated drug resistance: transporter specificity and structure–activity relationship. Cancer Chemother Pharmacol 60(6):789–797CrossRefPubMedGoogle Scholar
  22. Maliepaard M, van Gastelen MA, de Jong LA, Pluim D, van Waardenburg RCAM, Ruevekamp-Helmers MC, Floot BGJ, Schellens JHM (1999) Overexpression of the BCRP/MXR/ABCP gene in a topotecan-selected ovarian tumor cell line. Cancer Res 59(18):4559–4563PubMedGoogle Scholar
  23. Maliepaard M, Scheffer GL, Faneyte IF, van Gastelen MA, Pijnenborg ACLM, Schinkel AH, van de Vijver MJ, Scheper RJ, Schellens JHM (2001) Subcellular localization and distribution of the breast cancer resistance protein transporter in normal human tissues. Cancer Res 61(8):3458–3464PubMedGoogle Scholar
  24. Miyake K, Mickley L, Litman T, Zhan Z, Robey R, Cristensen B, Brangi M, Greenberger L, Dean M, Fojo T (1999) Molecular cloning of cDNAs which are highly overexpressed in mitoxantrone-resistant cells. Cancer Res 59(1):8–13PubMedGoogle Scholar
  25. Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (1998) Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 19(14):1639–1662CrossRefGoogle Scholar
  26. Nakanishi T, Doyle LA, Hassel B, Wei Y, Bauer KS, Wu S, Pumplin DW, Fang HB, Ross DD (2003) Functional characterization of human breast cancer resistance protein (BCRP, ABCG2) expressed in the oocytes of Xenopus laevis. Mol Pharmacol 64(6):1452–1462CrossRefPubMedGoogle Scholar
  27. Nandi S, Bagchi MC (2010) 3D-QSAR and molecular docking studies of 4-anilinoquinazoline derivatives: a rational approach to anticancer drug design. Mol Divers 14(1):27–38CrossRefPubMedGoogle Scholar
  28. Nicolle E, Boccard J, Guilet D, Dijoux-Franca M-G, Zelefac F, Macalou S, Grosselin J, Schmidt J, Carrupt P-A, Di Pietro A (2009a) Breast cancer resistance protein (BCRP/ABCG2): new inhibitors and QSAR studies by a 3D linear solvation energy approach. Eur J Pharm Sci 38(1):39–46CrossRefPubMedGoogle Scholar
  29. Nicolle E, Boccard J, Guilet D, Dijoux-Franca MG, Zelefac F, Macalou S, Grosselin J, Schmidt J, Carrupt PA, Di Pietro A (2009b) Breast cancer resistance protein (BCRP/ABCG2): new inhibitors and QSAR studies by a 3D linear solvation energy approach. Eur J Pharm Sci 38(1):39–46CrossRefPubMedGoogle Scholar
  30. Pick A, Müller H, Wiese M (2008) Structure–activity relationships of new inhibitors of breast cancer resistance protein (ABCG2). Bioorg Med Chem 16(17):8224–8236CrossRefPubMedGoogle Scholar
  31. Pick A, Müller H, Wiese M (2010) Novel lead for potent inhibitors of breast cancer resistance protein (BCRP). Bioorg Med Chem Lett 20(1):180–183CrossRefPubMedGoogle Scholar
  32. Pick A, Müller H, Mayer R, Haenisch B, Pajeva IK, Weigt M, Bönisch H, Müller CE, Wiese M (2011) Structure–activity relationships of flavonoids as inhibitors of breast cancer resistance protein (BCRP). Bioorg Med Chem 19(6):2090–2102CrossRefPubMedGoogle Scholar
  33. Powell MJD (1977) Restart procedures for the conjugate gradient method. Math Program 12(1):241–254CrossRefGoogle Scholar
  34. Robey RW, Medina-Pérez WY, Nishiyama K, Lahusen T, Miyake K, Litman T, Senderowicz AM, Ross DD, Bates SE (2001) Overexpression of the ATP-binding cassette half-transporter, ABCG2 (Mxr/BCrp/ABCP1), in flavopiridol-resistant human breast cancer cells. Clin Cancer Res 7(1):145–152PubMedGoogle Scholar
  35. Ross DD, Karp JE, Chen TT, Doyle LA (2000) Expression of breast cancer resistance protein in blast cells from patients with acute leukemia. Blood 96(1):365–368PubMedGoogle Scholar
  36. Singh U, Gangwal RP, Dhoke GV, Prajapati R, Damre M, Sangamwar AT (2012) 3D-QSAR and molecular docking analysis of (4-piperidinyl)-piperazines as acetyl-CoA carboxylases inhibitors. Arabian J Chem. doi: 10.1016/j.arabjc.2012.10.023 Google Scholar
  37. Szakács G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM (2006) Targeting multidrug resistance in cancer. Nat Rev Drug Discov 5(3):219–234CrossRefPubMedGoogle Scholar
  38. Valdameri G, Genoux-Bastide E, Peres B, Gauthier C, Guitton J, Terreux R, Winnischofer SMB, Rocha MEM, Boumendjel A, Di Pietro A (2012) Substituted chromones as highly-potent nontoxic inhibitors, specific for the breast cancer resistance protein. J Med Chem 55:966–970CrossRefPubMedGoogle Scholar
  39. van der Kolk DM, Vellenga E, Scheffer GL, Muller M, Bates SE, Scheper RJ, de Vries EGE (2002) Expression and activity of breast cancer resistance protein (BCRP) in de novo and relapsed acute myeloid leukemia. Blood 99(10):3763–3770CrossRefPubMedGoogle Scholar
  40. Volk EL, Farley KM, Wu Y, Li F, Robey RW, Schneider E (2002) Overexpression of wild-type breast cancer resistance protein mediates methotrexate resistance. Cancer Res 62(17):5035–5040PubMedGoogle Scholar
  41. Wang X, Furukawa T, Nitanda T, Okamoto M, Sugimoto Y, Akiyama SI, Baba M (2003) Breast cancer resistance protein (BCRP/ABCG2) induces cellular resistance to HIV-1 nucleoside reverse transcriptase inhibitors. Mol Pharmacol 63(1):65–72CrossRefPubMedGoogle Scholar
  42. Xu J, Liu Y, Yang Y, Bates S, Zhang JT (2004) Characterization of oligomeric human half-ABC transporter ATP-binding cassette G2. J Biol Chem 279(19):19781CrossRefPubMedGoogle Scholar
  43. Zhang S, Yang X, Coburn RA, Morris ME (2005) Structure activity relationships and quantitative structure activity relationships for the flavonoid-mediated inhibition of breast cancer resistance protein. Biochem Pharmacol 70(4):627–639CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Kanchan Khandelwal
    • 1
  • Rahul Prakashchand Gangwal
    • 1
  • Udghosh Singh
    • 1
  • Rameshwar Prajapati
    • 1
  • Mangesh V. Damre
    • 1
  • Abhay T. Sangamwar
    • 1
    Email author
  1. 1.Department of PharmacoinformaticsNational Institute of Pharmaceutical Education and Research (NIPER)MohaliIndia

Personalised recommendations