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Current Cancer Drug Targets

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ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

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Research Article

Grid-independent Descriptors (GRIND) Analysis and SAR Guided Molecular Docking Studies to Probe Selectivity Profiles of Inhibitors of Multidrug Resistance Transporters ABCB1 and ABCG2

Author(s): Talha Shafi and Ishrat Jabeen

Volume 17, Issue 2, 2017

Page: [177 - 190] Pages: 14

DOI: 10.2174/1568009616666160901094140

Price: $65

Abstract

Background: ATP-binding cassette (ABC) transporters, P-glycoprotein (P-gp, ABCB1) and breast cancer resistance protein (BCRP/ABCG2) are major determinants of pharmacokinetic, safety and efficacy profiles of drugs thereby effluxing a broad range of endogenous substances across the plasma membrane. Overexpression of these transporters in various tumors is also implicated in the development of multidrug resistance (MDR) and thus, hampers the success of cancer chemotherapy. Modulators of these efflux transporters in combination with chemotherapeutics could be a promising concept to increase the effective intracellular concentration of anticancer drugs. However, broad and overlapped specificity for substrates and modulators of ABCB1 and ABCG2, merely induce toxicity and unwanted drug-drug interactions and thus, lead to late-stage failure of drugs.

Objective: In present investigation, we aim to identify specific 3D structural requirements for selective inhibition of ABCB1 and ABCG2 transport function.

Method: GRID Independent Molecular Descriptor (GRIND) models of selective inhibitors of both transporters have been developed, using their most probable binding conformations obtained from molecular docking protocol.

Results: Our results demonstrated a dominant role of molecular shape and different H-bonding patterns in drug-ABCB1/ABCG2 selective interactions. Moreover, distinct distances of different pharmacophoric features from steric hot spots of the molecules provided a strong basis of selectivity for both transporters. Additionally, our results suggested the presence of two H-bond donors at a distance of 8.4-8.8 Å in selective modulators of ABCG2.

Conclusion: Our findings concluded that molecular shape along with three dimensional pattern of Hbonding in MDR modulators play a critical role in determining the selectivity between the two targets.

Keywords: Multidrug Resistance Protein 1 (MDR1), Breast Cancer Resistance Protein (BCRP), multidrug resistance, grind, molecular docking, selectivity profiling.

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[1]
Szakacs, G.; Paterson, J.K.; Ludwig, J.A.; Booth-Genthe, C.; Gottesman, M.M. Targeting multidrug resistance in cancer. Nat. Rev. Drug Discov., 2006, 5(3), 219-234.
[2]
Gottesman, M.M. Mechanisms of cancer drug resistance. Annu. Rev. Med., 2002, 53(1), 615-627.
[3]
(a)Jonker, J.W.; Smit, J.W.; Brinkhuis, R.F.; Maliepaard, M.; Beijnen, J.H.; Schellens, J.H.; Schinkel, A.H. Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan. J. Natl. Cancer Inst., 2000, 92(20), 1651-1656.
(b)Kruijtzer, C.M.; Beijnen, J.H.; Rosing, H.; ten Bokkel Huinink, W.W.; Schot, M.; Jewell, R.C.; Paul, E.M.; Schellens, J.H. Increased oral bioavailability of topotecan in combination with the breast cancer resistance protein and P-glycoprotein inhibitor GF120918. J. Clin. Oncol., 2002, 20(13), 2943-2950.
[4]
(a)Stewart, C.F.; Leggas, M.; Schuetz, J.D.; Panetta, J.C.; Cheshire, P.J.; Peterson, J.; Daw, N.; Jenkins, J.J., III; Gilbertson, R.; Germain, G.S.; Harwood, F.C.; Houghton, P.J. Gefitinib enhances the antitumor activity and oral bioavailability of irinotecan in mice. Cancer Res., 2004, 64(20), 7491-7499.
(b) Breedveld, P.; Pluim, D.; Cipriani, G.; Wielinga, P.; van Tellingen, O.; Schinkel, A.H.; Schellens, J.H. The effect of Bcrp1 (Abcg2) on the in vivo pharmacokinetics and brain penetration of imatinib mesylate (Gleevec): implications for the use of breast cancer resistance protein and P-glycoprotein inhibitors to enable the brain penetration of imatinib in patients. Cancer Res., 2005, 65(7), 2577-2582.
(c) Elmeliegy, M.A.; Carcaboso, A.M.; Tagen, M.; Bai, F.; Stewart, C.F. Role of ATP-binding cassette and solute carrier transporters in erlotinib CNS penetration and intracellular accumulation. Clin. Cancer Res., 2011, 17(1), 89-99.
[5]
(a) Wattel, E.; Solary, E.; Hecquet, B.; Caillot, D.; Ifrah, N.; Brion, A.; Milpied, N.; Janvier, M.; Guerci, A.; Rochant, H.; Cordonnier, C.; Dreyfus, F.; Veil, A.; Hoang-Ngoc, L.; Stoppa, A.M.; Gratecos, N.; Sadoun, A.; Tilly, H.; Brice, P.; Lioure, B.; Desablens, B.; Pignon, B.; Abgrall, J.P.; Leporrier, M.; Fenaux, P. Quinine improves results of intensive chemotherapy (IC) in myelodysplastic syndromes (MDS) expressing P-glycoprotein (PGP). Updated results of a randomized study. Groupe Francais des Myelodysplasies (GFM) and Groupe GOELAMS. Adv. Exp. Med. Biol., 1999, 457, 35-46.
(b) Minderman, H.; O’Loughlin, K.L.; Pendyala, L.; Baer, M.R. VX-710 (biricodar) increases drug retention and enhances chemosensitivity in resistant cells overexpressing P-glycoprotein, multidrug resistance protein, and breast cancer resistance protein. Clin. Cancer Res., 2004, 10(5), 1826-1834.
(c) Pusztai, L.; Wagner, P.; Ibrahim, N.; Rivera, E.; Theriault, R.; Booser, D.; Symmans, F.W.; Wong, F.; Blumenschein, G.; Fleming, D.R.; Rouzier, R.; Boniface, G.; Hortobagyi, G.N. Phase II study of tariquidar, a selective P-glycoprotein inhibitor, in patients with chemotherapy-resistant, advanced breast carcinoma. Cancer, 2005, 104(4), 682-691.
[6]
von Richter, O.; Burk, O.; Fromm, M.F.; Thon, K.P.; Eichelbaum, M.; Kivisto, K.T. Cytochrome P450 3A4 and P-glycoprotein expression in human small intestinal enterocytes and hepatocytes: a comparative analysis in paired tissue specimens. Clin. Pharmacol. Ther., 2004, 75(3), 172-183.
[7]
Hoffmaster, K.A.; Turncliff, R.Z.; LeCluyse, E.L.; Kim, R.B.; Meier, P.J.; Brouwer, K.L. P-glycoprotein expression, localization, and function in sandwich-cultured primary rat and human hepatocytes: relevance to the hepatobiliary disposition of a model opioid peptide. Pharm. Res., 2004, 21(7), 1294-1302.
[8]
Karssen, A.M.; Meijer, O.; Pons, D.; De Kloet, E.R. Localization of mRNA expression of P-glycoprotein at the blood-brain barrier and in the hippocampus. Ann. N. Y. Acad. Sci., 2004, 1032, 308-311.
[9]
Molsa, M.; Heikkinen, T.; Hakkola, J.; Hakala, K.; Wallerman, O.; Wadelius, M.; Wadelius, C.; Laine, K. Functional role of P-glycoprotein in the human blood-placental barrier. Clin. Pharmacol. Ther., 2005, 78(2), 123-131.
[10]
(a) Linton, K.J. Structure and function of ABC transporters. Physiology (Bethesda), 2007, 22, 122-130.
(b) Hill, C.R.; Jamieson, D.; Thomas, H.D.; Brown, C.D.; Boddy, A.V.; Veal, G.J. Characterisation of the roles of ABCB1, ABCC1, ABCC2 and ABCG2 in the transport and pharmacokinetics of actinomycin D in vitro and in vivo. Biochem. Pharmacol., 2013, 85(1), 29-37.
(c) Hu, M.; To, K.K.; Mak, V.W.; Tomlinson, B. The ABCG2 transporter and its relations with the pharmacokinetics, drug interaction and lipid-lowering effects of statins. Expert Opin. Drug Metab. Toxicol., 2011, 7(1), 49-62.
dHu, M.; Tomlinson, B. Evaluation of the pharmacokinetics and drug interactions of the two recently developed statins, rosuvastatin and pitavastatin. Expert Opin. Drug Metab. Toxicol., 2014, 10(1), 51-65.
[11]
(a) van Waterschoot, R.A.; ter Heine, R.; Wagenaar, E.; van der Kruijssen, C.M.; Rooswinkel, R.W.; Huitema, A.D.; Beijnen, J.H.; Schinkel, A.H. Effects of cytochrome P450 3A (CYP3A) and the drug transporters P-glycoprotein (MDR1/ABCB1) and MRP2 (ABCC2) on the pharmacokinetics of lopinavir. Br. J. Pharmacol., 2010, 160(5), 1224-1233.
(b) Windisch, A.; Timin, E.; Schwarz, T.; Stork-Riedler, D.; Erker, T.; Ecker, G.; Hering, S. Trapping and dissociation of propafenone derivatives in HERG channels. Br. J. Pharmacol., 2011, 162(7), 1542-1552.
(c) Zhang, S.; Zhou, Z.; Gong, Q.; Makielski, J.C.; January, C.T. Mechanism of block and identification of the verapamil binding domain to HERG potassium channels. Circ. Res., 1999, 84(9), 989-998.
[12]
(a) Li, J.; Jaimes, K.F.; Aller, S.G. Refined structures of mouse P-glycoprotein. Protein Sci., 2014, 23(1), 34-46.
(b) Szewczyk, P.; Tao, H.; McGrath, A.P.; Villaluz, M.; Rees, S.D.; Lee, S.C.; Doshi, R.; Urbatsch, I.L.; Zhang, Q.; Chang, G. Snapshots of ligand entry, malleable binding and induced helical movement in P-glycoprotein. Acta Crystallogr. D Biol. Crystallogr., 2015, 7(Pt 3), 732-741.
[13]
Demel, M.A.; Schwaha, R.; Kramer, O.; Ettmayer, P.; Haaksma, E.E.; Ecker, G.F. In silico prediction of substrate properties for ABC-multidrug transporters. Expert Opin. Drug Metab. Toxicol., 2008, 4(9), 1167-1180.
[14]
(a) Allen, J.D.; van Loevezijn, A.; Lakhai, J.M.; van der Valk, M.; van Tellingen, O.; Reid, G.; Schellens, J.H.; Koomen, G-J.; Schinkel, A.H. Potent and specific inhibition of the breast cancer resistance protein multidrug transporter in vitro and in mouse intestine by a novel analogue of fumitremorgin C 1 this work was supported in part by grant NKI 97-1433 from the Dutch Cancer Society (to AHS). Synthesis investigations by A. v. L. and GJ. K. were supported by the Netherlands Research Council for Chemical Sciences (NWO/CW) and the Netherlands Technology Foundation (STW). 1. Mol. Cancer Ther., 2002, 1(6), 417-425.
(b) Boumendjel, A.; Macalou, S.; Valdameri, G.; Pozza, A.; Gauthier, C.; Arnaud, O.; Nicolle, E.; Magnard, S.; Falson, P.; Terreux, R.; Carrupt, P.A.; Payen, L.; Di Pietro, A. Targeting the multidrug ABCG2 transporter with flavonoidic inhibitors: in vitro optimization and in vivo validation. Curr. Med. Chem., 2011, 18(22), 3387-3401.
(c) Fox, E.; Bates, S.E. Tariquidar (XR9576): a P-glycoprotein drug efflux pump inhibitor. Expert Rev. Anticancer Ther., 2007, 7(4), 447-459.
[15]
Pastor, M.; Cruciani, G.; McLay, I.; Pickett, S.; Clementi, S. GRid-INdependent descriptors (GRIND): a novel class of alignment-independent three-dimensional molecular descriptors. J. Med. Chem., 2000, 43(17), 3233-3243.
[16]
Duran, A.; Martinez, G.C.; Pastor, M. Development and validation of AMANDA, a new algorithm for selecting highly relevant regions in Molecular Interaction Fields. J. Chem. Inf. Model., 2008, 48(9), 1813-1823.
[17]
Jabeen, I.; Wetwitayaklung, P.; Klepsch, F.; Parveen, Z.; Chiba, P.; Ecker, G.F. Probing the stereoselectivity of P-glycoprotein-synthesis, biological activity and ligand docking studies of a set of enantiopure benzopyrano[3,4-b][1,4]oxazines. Chem. Commun. (Camb.), 2011, 47(9), 2586-2588.
[18]
Magrane, M.; Consortium, U. UniProt Knowledgebase: a hub of integrated protein data. Database (Oxford), 2011, 2011, bar009..
[19]
Sievers, F.; Wilm, A.; Dineen, D.; Gibson, T.J.; Karplus, K.; Li, W.; Lopez, R.; McWilliam, H.; Remmert, M.; Soding, J.; Thompson, J.D.; Higgins, D.G. Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol. Syst. Biol., 2011, 7, 539.
[20]
Waterhouse, A.M.; Procter, J.B.; Martin, D.M.; Clamp, M.; Barton, G.J. Jalview Version 2--a multiple sequence alignment editor and analysis workbench. Bioinformatics, 2009, 25(9), 1189-1191.
[21]
Aller, S.G.; Yu, J.; Ward, A.; Weng, Y.; Chittaboina, S.; Zhuo, R.; Harrell, P.M.; Trinh, Y.T.; Zhang, Q.; Urbatsch, I.L. Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science, 2009, 323(5922), 1718-1722.
[22]
Shen, M.Y.; Sali, A. Statistical potential for assessment and prediction of protein structures. Protein Sci., 2006, 15(11), 2507-2254.
[23]
Colovos, C.; Yeates, T.O. Verification of protein structures: patterns of nonbonded atomic interactions. Protein Sci., 1993, 2(9), 1511-1519.
[24]
Lovell, S.C.; Davis, I.W.; Arendall, W.B., III; de Bakker, P.I.; Word, J.M.; Prisant, M.G.; Richardson, J.S.; Richardson, D.C. Structure validation by Calpha geometry: phi, psi and Cbeta deviation. Proteins, 2003, 50(3), 437-450.
[25]
Jones, G.; Willett, P.; Glen, R.C. Molecular recognition of receptor sites using a genetic algorithm with a description of desolvation. J. Mol. Biol., 1995, 245(1), 43-53.
[26]
Rosenberg, M.F.; Velarde, G.; Ford, R.C.; Martin, C.; Berridge, G.; Kerr, I.D.; Callaghan, R.; Schmidlin, A.; Wooding, C.; Linton, K.J. Repacking of the transmembrane domains of P‐glycoprotein during the transport ATPase cycle. EMBO J., 2001, 20(20), 5615-5625.
[27]
(a)Cramer, J.; Kopp, S.; Bates, S.E.; Chiba, P.; Ecker, G.F. Multispecificity of drug transporters: probing inhibitor selectivity for the human drug efflux transporters ABCB1 and ABCG2. ChemMedChem, 2007, 2(12), 1783-1788.
(b)Kühnle, M.; Egger, M.; Müller, C.; Mahringer, A.; Bernhardt, G.n.; Fricker, G.; König, B.; Buschauer, A. Potent and selective inhibitors of breast cancer resistance protein (ABCG2) derived from the p-glycoprotein (ABCB1) modulator tariquidar. J. Med. Chem., 2009, 52(4), 1190-1197.
[28]
(a)Jabeen, I.; Pleban, K.; Rinner, U.; Chiba, P.; Ecker, G.F. Structure–activity relationships, ligand efficiency, and lipophilic efficiency profiles of benzophenone-type inhibitors of the multidrug transporter p-glycoprotein. J. Med. Chem., 2012, 55(7), 3261-3273.
(b)Klepsch, F.; Chiba, P.; Ecker, G.F. Exhaustive Sampling of Docking Poses Reveals Binding Hypotheses for Propafenone Type Inhibitors of P-Glycoprotein. PLOS Comput. Biol., 2011, 7(5), e1002036.
(c)Chiba, P.; Tell, B.; Jager, W.; Richter, E.; Hitzler, M.; Ecker, G. Studies on propafenone-type modulators of multidrug-resistance IV1): synthesis and pharmacological activity of 5-hydroxy and 5-benzyloxy derivatives. Arch. Pharm. (Weinheim), 1997, 330(11), 343-347.
[29]
Chang, C.; Ekins, S.; Bahadduri, P.; Swaan, P.W. Pharmacophore-based discovery of ligands for drug transporters. Adv. Drug Deliv. Rev., 2006, 58(12-13), 1431-1450.
[30]
Rosenberg, M.F.; Bikadi, Z.; Chan, J.; Liu, X.; Ni, Z.; Cai, X.; Ford, R.C.; Mao, Q. The human breast cancer resistance protein (BCRP/ABCG2) shows conformational changes with mitoxantrone. Structure (London, England : 1993),, 2010, 14(8), 482-493.
[31]
(a)Ecker, G.F.; Csaszar, E.; Kopp, S.; Plagens, B.; Holzer, W.; Ernst, W.; Chiba, P. Identification of ligand-binding regions of p-glycoprotein by activated-pharmacophore photoaffinity labeling and matrix-assisted laser desorption/ionization–time-of-flight mass spectrometry. Mol. Pharmacol., 2002, 61(3), 637-648.
(b)Pleban, K.; Kopp, S.; Csaszar, E.; Peer, M.; Hrebicek, T.; Rizzi, A.; Ecker, G.F.; Chiba, P. P-glycoprotein substrate binding domains are located at the transmembrane domain/transmembrane domain interfaces: a combined photoaffinity labeling-protein homology modeling approach. Mol. Pharmacol., 2005, 67(2), 365-374.
[32]
(a)Loo, T.W.; Clarke, D.M. Defining the drug-binding site in the human multidrug resistance P-glycoprotein using a methan-ethiosulfonate analog of verapamil, MTS-verapamil. J. Biol. Chem., 2001, 276(18), 14972-14979.
(b)Loo, T.W.; Bartlett, M.C.; Clarke, D.M. Methanethiosulfonate derivatives of rhodamine and verapamil activate human P-glycoprotein at different sites. J. Biol. Chem., 2003, 278(50), 50136-50141.
[33]
Sareila, O.; Korhonen, R.; Kärpänniemi, O.; Nieminen, R.; Kankaanranta, H.; Moilanen, E. JAK inhibitors AG-490 and WHI-P154 decrease IFN-γ-induced iNOS expression and NO production in macrophages. Mediators Inflamm., 2006, 2006(2), 16161.
[34]
Bollag, G.; Hirth, P.; Tsai, J.; Zhang, J.; Ibrahim, P.N.; Cho, H.; Spevak, W.; Zhang, C.; Zhang, Y.; Habets, G.; Burton, E.A.; Wong, B.; Tsang, G.; West, B.L.; Powell, B.; Shellooe, R.; Marimuthu, A.; Nguyen, H.; Zhang, K.Y.; Artis, D.R.; Schlessinger, J.; Su, F.; Higgins, B.; Iyer, R.; D’Andrea, K.; Koehler, A.; Stumm, M.; Lin, P.S.; Lee, R.J.; Grippo, J.; Puzanov, I.; Kim, K.B.; Ribas, A.; McArthur, G.A.; Sosman, J.A.; Chapman, P.B.; Flaherty, K.T.; Xu, X.; Nathanson, K.L.; Nolop, K. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature, 2010, 467(7315), 596-599.
[35]
(a)Vispute, S.G.; Cheng, J.; Sun, Y.; Sodani, K.S.; Singh, S.; Pan, Y.; Talele, T.; Ashby, C.R., Jr; Chen, Z. Vemurafenib (PLX4032, Zelboraf ®), a BRAF inhibitor, modulates ABCB1-, ABCG2-, and ABCC10-mediated multidrug resistance. J. Cancer Res. Updates, 2013, 2, 11.
(b)Zhang, H.; Zhang, Y.K.; Wang, Y.J.; Kathawala, R.J.; Patel, A.; Zhu, H.; Sodani, K.; Talele, T.T.; Ambudkar, S.V.; Chen, Z.S.; Fu, L.W. WHI-P154 enhances the chemotherapeutic effect of anticancer agents in ABCG2-overexpressing cells. Cancer Sci., 2014, 105(8), 1071-1078.
[36]
Caron, G.; Ermondi, G. Influence of conformation on GRIND-based three-dimensional quantitative structure−activity relationship (3D-QSAR). J. Med. Chem., 2007, 50(20), 5039-5042.
[37]
Baroni, M.; Costantino, G.; Cruciani, G.; Riganelli, D.; Valigi, R.; Clementi, S. Generating optimal linear PLS estimations (GOLPE): an advanced chemometric tool for handling 3D-QSAR problems. Mol. Inform., 1993, 12(1), 9-20.
[38]
Jabeen, I.; Wetwitayaklung, P.; Chiba, P.; Pastor, M.; Ecker, G.F. 2D- and 3D-QSAR studies of a series of benzopyranes and benzopyrano[3,4b][1,4]-oxazines as inhibitors of the multidrug transporter P-glycoprotein. J. Comput. Aided Mol. Des., 2013, 27(2), 161-171.
[39]
Crivori, P.; Reinach, B.; Pezzetta, D.; Poggesi, I. Computational models for identifying potential P-glycoprotein substrates and inhibitors. Mol. Pharm., 2006, 3(1), 33-44.
[40]
Broccatelli, F.; Carosati, E.; Neri, A.; Frosini, M.; Goracci, L.; Oprea, T.I.; Cruciani, G. A Novel Approach for predicting p-glycoprotein (ABCB1) inhibition using molecular interaction fields. J. Med. Chem., 2011, 54(6), 1740-1751.
[41]
Boccard, J.; Bajot, F.; Di Pietro, A.; Rudaz, S.; Boumendjel, A.; Nicolle, E.; Carrupt, P.A. A 3D linear solvation energy model to quantify the affinity of flavonoid derivatives toward P-glycoprotein. Eur. J. Pharm. Sci., 2009, 36(2-3), 254-264.
[42]
Shukla, S.; Kouanda, A.; Silverton, L.; Talele, T.T.; Ambudkar, S.V. Pharmacophore modeling of nilotinib as an inhibitor of ATP-binding cassette drug transporters and BCR-ABL kinase using a three-dimensional quantitative structure-activity relationship approach. Mol. Pharm., 2014, 11(7), 2313-2322.

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