Some substrates of P-glycoprotein targeting β-amyloid clearance by quantitative structure-activity relationship (QSAR)/membrane-interaction (MI)-QSAR analysis
Affiliation(s)
State Key Laboratory of Pharmaceutical Biotechnology, Life College, Nanjing University, Nanjing, China.
State Key Laboratory of Pharmaceutical Biotechnology, Life College, Nanjing University, Nanjing, China.
ABSTRACT
The pathogenesis of Alzheimer’s disease (AD) putatively involves a compromised blood-brain barrier (BBB). In particular, the importance of brain-to-blood transport of brain-derived metabolites across the BBB has gained increasing attention as a potential mechanism in the pathogenesis of neurodegenerative disorders such as AD, which is characterized by the aberrant polymerization and accumulation of specific misfolded proteins, particularly β-amyloid (Aβ), a neuropathological hallmark of AD. P-glycoprotein (P-gp), a major component of the BBB, plays a role in the etiology of AD through Aβ clearance from the brain. Our QSAR models on a series of purine-type and propafenone-type substrates of P-gp showed that the interaction between P-gp and its modulators depended on Molar Refractivity, LogP, and Shape Attribute of drugs it transports. Meanwhile, another model on BBB partitioning of some compounds revealed that BBB partitioning relied upon the polar surface area, LogP, Balaban Index, the strength of a molecule combined with the membrane-water complex, and the changeability of the structure of a solute-membrane-water complex. The predictive model on BBB partitioning contributes to the discovery of some molecules through BBB as potential AD therapeutic drugs. Moreover, the interaction model of P-gp and modulators for treatment of multidrug resistance (MDR) indicates the discovery of some molecules to increase Aβ clearance from the brain and reduce Aβ brain accumulation by regulating BBB P-gp in the early stages of AD. The mechanism provides a new insight into the therapeutic strategy for AD.
Cite this paper
Zhu, T. , Chen, J. and Yang, J. (2013) Some substrates of P-glycoprotein targeting β-amyloid clearance by quantitative structure-activity relationship (QSAR)/membrane-interaction (MI)-QSAR analysis. Advances in Bioscience and Biotechnology, 4, 872-895. doi: 10.4236/abb.2013.49116.
Zhu, T. , Chen, J. and Yang, J. (2013) Some substrates of P-glycoprotein targeting β-amyloid clearance by quantitative structure-activity relationship (QSAR)/membrane-interaction (MI)-QSAR analysis. Advances in Bioscience and Biotechnology, 4, 872-895. doi: 10.4236/abb.2013.49116.
References
[1] Cheng, Z., Zhang, J., Liu, H., Li, Y., Zhao, Y. and Yang, E. (2010) Central nervous system penetration for small molecule therapeutic agents does not increase in multiple sclerosis-and Alzheimer’s disease-related animal models despite reported blood-brain barrier disruption. Drug Metabolism & Disposition, 38, 1355-1361. doi:10.1124/dmd.110.033324 [2] Chen, Y., Zhu, Q.J., Pan, J., Yang, Y. and Wu, X.P. (2009) A prediction model for blood-brain barrier permeation and analysis on its parameter biologically. Computer Methods and Programs in Biomedicine, 95, 280-287. doi:10.1016/j.cmpb.2009.03.006 [3] Miklossy, J. (2011) Alzheimer’s disease—A neurospirochetosis. Analysis of the evidence following Koch’s and Hill’s criteria. Journal of Neuroinflammation, 8, 90. [4] Inoue, M., Konno, T., Tainaka, K., Nakata, E., Yoshida, H.O. and Morii, T. (2012) Positional effects of phosphorylation on the stability and morphology of tau-related amyloid fibrils. Biochemistry, 51, 1396-1406. [5] Daebel, V., Chinnathambi, S., Biernat, J., Schwalbe, M., Habenstein, B., Loquet, A., Akoury, E., Tepper, K., Müller, H., Baldus, M., Griesinger, C., Zweckstetter, M., Mandelkow, E., Vijayan, V. and Lange, A. (2012) β-sheet core of tau paired helical filaments revealed by solid-state NMR. Journal of the American Chemical Society, 134, 13982-13989. doi:10.1021/ja305470p [6] Jeynes, B. and Provias, J. (2011) An investigation into the role of p-glycoprotein in Alzheimer’s disease lesion pathogenesis. Neuroscience Letters, 487, 389-393. doi:10.1016/j.neulet.2010.10.063 [7] Vogelgesang, S., Jedlitschky, G., Brenn, A. and Walker, L.C. (2011) The role of the ATP-binding cassette transporter p-glycoprotein in the transport of β-amyloid across the blood-brain barrier. Current Pharmaceutical Design, 17, 2778-2786. doi:10.2174/138161211797440168 [8] Bartels, A.L. (2011) Blood-brain barrier p-glycoprotein function in neurodegenerative disease. Current Pharmaceutical Design, 17, 2771-2777. doi:10.2174/138161211797440122 [9] Gottesman, M.M. and Pastan, I. (1993) Biochemistry of multidrug resistance mediated by the multidrug transporter. Annual Review of Biochemistry, 62, 385-427. [10] Kast, C., Canfield, V., Levenson, R. and Gros, P. (1996) Transmembrane organization of mouse p-glycoprotein determined by epitope insertion and immunofluorescence. The Journal of Biological Chemistry, 271, 9240-9248. [11] Bendayan, R., Lee, G. and Bendayan, M. (2002) Functional expression and localization of p-glycoprotein at the blood brain barrier. Microscopy Research and Technique, 57, 365-380. [12] Abuznait, A.H., Cain. C., Ingram, D., Burk, D. and Kaddoumi, A. (2011) Up-regulation of p-glycoprotein reduces intracellular accumulation of beta amyloid: Investigation of p-glycoprotein as a novel therapeutic target for Alzheimer’s disease. Journal of Pharmacy and Pharmacology, 63, 1111-1118. doi:10.1111/j.2042-7158.2011.01309.x [13] Kothandan, G., Gadhe, C.G., Madhavan, T., Choi, C.H. and Cho, S.J. (2011) Docking and 3D-QSAR (quantitative structure activity relationship) studies of flavones, the potent inhibitors of p-glycoprotein targeting the nucleotide binding domain. European Journal of Medicinal Chemistry, 46, 4078-4088. doi:10.1016/j.ejmech.2011.06.008 [14] Hartz, A.M., Miller, D.S. and Bauer, B. (2010) Restoring blood-brain barrier p-glycoprotein reduces brain amyloid-beta in a mouse model of Alzheimer’s disease. Molecular Pharmacology, 77, 715-723. doi:10.1124/mol.109.061754 [15] Jabeen, I., Pleban, K., Rinner, U., Chiba, P. and Ecker, G.F. (2012) Structure-activity relationships, ligand efficiency, and lipophilic efficiency profiles of benzophenone-type inhibitors of the multidrug transporter p-glycoprotein. Journal of Medicinal Chemistry, 55, 3261-3273. [16] Stouch, T.R. and Gudmundsson, O. (2002) Progress in understanding the structure-activity relationships of pglycoprotein. Advanced Drug Delivery Reviews, 54, 315-328. doi:10.1016/S0169-409X(02)00006-6 [17] Sharom, F.J. (1997) The p-glycoprotein efflux pump: How does it transport drugs? The Journal of Membrane Biology, 160, 161-175. doi:10.1007/s002329900305 [18] Li, Y., Wang, Y.H., Yang, L., Zhang, S.W., Liu, C.H. and Yang, S.L. (2005) Comparison of steroid substrates and inhibitors of p-glycoprotein by 3D-QSAR analysis. Journal of Molecular Structure, 733, 111-118. [19] Wang, R.B., Kuo, C.L., Lien, L.L. and Lien, E.J. (2003) Structure-activity relationship: Analyses of p-glycoprotein substrates and inhibitors. Journal of Clinical Pharmacy and Therapeutics, 28, 203-228. [20] Wang, Y.H., Li, Y., Yang, S.L. and Yang, L. (2005) An in silico approach for screening flavonoids as p-glycoprotein inhibitors based on a Bayesian-regularized neural network. Journal of Computer-Aided Molecular Design, 19, 137-147. doi:10.1007/s10822-005-3321-5 [21] Chen, C. and Yang, J. (2006) MI-QSAR models for prediction of corneal permeability of organic compounds. Acta Pharmacologica Sinica, 27, 193-204. doi:10.1111/j.1745-7254.2006.00241.x [22] Kubinyi, H. (1995) Strategies and recent technologies in drug discovery. Pharmazie, 50, 647-662. [23] Wiese, M. and Pajeva, I.K. (2001) Structure-activity relationships of multidrug resistance reversers. Current Medicinal Chemistry, 8, 685-713. [24] Taub, M.E., Podila, L., Ely, D. and Almeida, I. (2005) Functional assessment of multiple p-glycoprotein (p-gp) probe substrates: Influence of cell line and modulator concentration on p-gp activity. Drug Metabolism & Disposition, 33, 1679-1687. doi:10.1124/dmd.105.005421 [25] Alka, K. (2003) C-QSAR: A database of 18000 QSARs and associated biological and physical data. Journal of Computer-Aided Molecular Design, 17, 187-196. [26] Kuo, C.L., Assefa, H., Kamath, S., Brzozowski, Z., Slawinski, J., Saczewski, F., Buolamwini, J.K. and Neamati, N. (2004) Application of CoMFA and CoMSIA 3D-QSAR and docking studies in optimization of mercaptobenzenesulfonamides as HIV-1 integrase inhibitors. Journal of Medicinal Chemistry, 47, 385-399. doi:10.1021/jm030378i [27] Cramer, R.D., Patterson, D.E. and Bunce, J.D. (1988) Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. Journal of the American Chemical Society, 110, 5959-5967. [28] Chen, L.J., Lian, G.P. and Han, L.J. (2007) Prediction of human skin permeability using artificial neural network (ANN) modeling. Acta Pharmacologica Sinica, 28, 591-600. [29] Dhainaut, A., Regnier, G., Tizot, A., Pierre A., Leonce, S., Guilbaud, N., Kraus-Berthier, L. and Atassi, G. (1996) New purines and purine analogs as modulators of multidrug resistance. Journal of Medicinal Chemistry, 39, 4099-4108. [30] Ford, J.M., Bruggemann, E.P., Pastan, I., Gottesman, M.M. and Hait, W.N. (1990) Cellular and biochemical characterization of thioxanthenes for revesal of multidrug resistance in human and murine cell lines. Cancer Research, 50, 1748-1756. [31] Schmid, D., Ecker, G., Kopp, S., Hitzler, M. and Chiba, P. (1999) Structure-activity relationship studies of propafenone analogs cased on p-glycoprotein ATPase activity measurements. Biochemical Pharmacology, 58, 1447-1456. doi:10.1016/S0006-2952(99)00229-4 [32] Karelson, M. (2000) Molecular descriptors in QSAR/ QSPR. John Wiley & Sons, New York. [33] Karelson, M., Lobanov, V.S. and Katritzky, A.R. (1996) Quantum-chemical descriptors in QSAR/QSPR studies. Chemical Reviews, 96, 1027-1044. [34] Ponce, Y.M., Garit, J.A., Torrens, F., Zaldivar, V.R. and Castro, E.A. (2004) Atom, atom-type, and total linear indices of the “molecular pseudograph’s atom adjacency matrix”: Application to QSPR/QSAR studies of organic compounds. Molecules, 9, 1100-1123. doi:10.3390/91201100 [35] Iyer, M., Mishra, R., Han, Y. and Hopfinger, A.J. (2002) Predicting blood-brain barrier partitioning of organic molecules using membrane-interaction QSAR analysis. Pharmaceutical Research, 19, 1611-1621. doi:10.1023/A:1020792909928 [36] Abraham, M.H., Chadha, H.S. and Mitchell, R.C. (1995) Hydrogen bonding. 36. Determination of blood-brain barrier distribution using octanol-water partition coefficients. Drug Design and Discovery, 13, 123-131. [37] Abraham, M.H., Takacs-Novak, K. and Mitchell, R.C. (1997) On the partition of ampholytes: Application to blood-brain distribution. Journal of Pharmaceutical Sciences, 86, 310-315. doi:10.1021/js960328j [38] Bassolino-Klimas, D., Alper, H.E. and Stouch, T.R. (1993) Solute diffusion in lipid bilayer membranes: An atomic level study by molecular dynamics simulation. Biochemistry, 32, 12624-12637. doi:10.1021/bi00210a010 [39] Ma, X.L., Chen, C. and Yang, J. (2005) Predictive model of blood-brain barrier penetration of organic compounds. Acta Pharmacologica Sinica, 26, 500-512. doi:10.1111/j.1745-7254.2005.00068.x [40] Ohtsuki, S., Ito, S. and Terasaki, T. (2010) Is p-glycoprotein involved in amyloid-β elimination across the blood-brain barrier in Alzheimer’s disease? Clinical Pharmacology & Therapeutics, 88, 443-445. [41] Aller, S.G., Yu, J., Ward, A., Weng, Y., Chittaboina, S., Zhuo, R., Harrell, P.M., Trinh, Y.T., Zhang, Q., Urbatsch, I.L. and Chang, G. (2009) Structure of p-glycoprotein reveals a molecular basis for poly-specific drug binding. Science, 323, 1718-1722. doi:10.1126/science.1168750 [42] Ambudkar, S.V., Lelong, I.H., Zhang, J., Cardarelli, C.O., Gottesman, M.M. and Pastan, I. (1992) Partial purification and reconstitution of the human multidrug-resistance pump: Characterization of the drug-stimulatable ATP hydrolysis. Proceedings of the National Academy of Sciences of the United States of America, 89, 8472-8476. [43] Shapiro, A.B. and Ling, V. (1994) ATPase activity of purified and reconstituted p-glycoprotein from Chinese hamster ovary cells. The Journal of Biological Chemistry, 269, 3745-3754. [44] Doige, C.A., Yu, X. and Sharom, F.J. (1993) The effects of lipids and detergents on ATPase-active p-glycoprotein. Biochimica et Biophysica Acta, 1146, 65-72. [45] Litman, T., Zeuthen, T., Skovsgaard, T. and Stein, W.D. (1997) Structure-activity relationships of p-glycoprotein interacting drugs: Kinetic characterization of their effects on ATPase activity. Biochimica et Biophysica Acta, 1361, 159-168. [46] Waterhouse, R.N. (2003) Determination of lipophilicity and its use as a predictor of blood-brain barrier penetration of molecular imaging agents. Molecular Imaging & Biology, 5, 376-389. doi:10.1016/j.mibio.2003.09.014 [47] Palmeira, A., Sousa, E., Fernandes, M.X., Pinto, M.M. and Vasconcelos, M.H. (2012) Multidrug resistance reversal effects of aminated thioxanthones and interaction with cytochrome P450 3A4. Journal of Pharmacy and Pharmaceutical sciences, 15, 31-45. [48] Higgins, C.F. and Gottesman, M.M. (1992) Is the multidrug transporter a flippase? Trends in Biochemical Sciences, 17, 18-21. [49] Nazer, B., Hong, S. and Selkoe, D.J. (2008) LRP promotes endocytosis and degradation, but not transcytosis, of the amyloid-beta peptide in a blood-brain barrier in vitro model. Neurobiology of Disease, 30, 94-102. doi:10.1016/j.nbd.2007.12.005
[1] Cheng, Z., Zhang, J., Liu, H., Li, Y., Zhao, Y. and Yang, E. (2010) Central nervous system penetration for small molecule therapeutic agents does not increase in multiple sclerosis-and Alzheimer’s disease-related animal models despite reported blood-brain barrier disruption. Drug Metabolism & Disposition, 38, 1355-1361. doi:10.1124/dmd.110.033324 [2] Chen, Y., Zhu, Q.J., Pan, J., Yang, Y. and Wu, X.P. (2009) A prediction model for blood-brain barrier permeation and analysis on its parameter biologically. Computer Methods and Programs in Biomedicine, 95, 280-287. doi:10.1016/j.cmpb.2009.03.006 [3] Miklossy, J. (2011) Alzheimer’s disease—A neurospirochetosis. Analysis of the evidence following Koch’s and Hill’s criteria. Journal of Neuroinflammation, 8, 90. [4] Inoue, M., Konno, T., Tainaka, K., Nakata, E., Yoshida, H.O. and Morii, T. (2012) Positional effects of phosphorylation on the stability and morphology of tau-related amyloid fibrils. Biochemistry, 51, 1396-1406. [5] Daebel, V., Chinnathambi, S., Biernat, J., Schwalbe, M., Habenstein, B., Loquet, A., Akoury, E., Tepper, K., Müller, H., Baldus, M., Griesinger, C., Zweckstetter, M., Mandelkow, E., Vijayan, V. and Lange, A. (2012) β-sheet core of tau paired helical filaments revealed by solid-state NMR. Journal of the American Chemical Society, 134, 13982-13989. doi:10.1021/ja305470p [6] Jeynes, B. and Provias, J. (2011) An investigation into the role of p-glycoprotein in Alzheimer’s disease lesion pathogenesis. Neuroscience Letters, 487, 389-393. doi:10.1016/j.neulet.2010.10.063 [7] Vogelgesang, S., Jedlitschky, G., Brenn, A. and Walker, L.C. (2011) The role of the ATP-binding cassette transporter p-glycoprotein in the transport of β-amyloid across the blood-brain barrier. Current Pharmaceutical Design, 17, 2778-2786. doi:10.2174/138161211797440168 [8] Bartels, A.L. (2011) Blood-brain barrier p-glycoprotein function in neurodegenerative disease. Current Pharmaceutical Design, 17, 2771-2777. doi:10.2174/138161211797440122 [9] Gottesman, M.M. and Pastan, I. (1993) Biochemistry of multidrug resistance mediated by the multidrug transporter. Annual Review of Biochemistry, 62, 385-427. [10] Kast, C., Canfield, V., Levenson, R. and Gros, P. (1996) Transmembrane organization of mouse p-glycoprotein determined by epitope insertion and immunofluorescence. The Journal of Biological Chemistry, 271, 9240-9248. [11] Bendayan, R., Lee, G. and Bendayan, M. (2002) Functional expression and localization of p-glycoprotein at the blood brain barrier. Microscopy Research and Technique, 57, 365-380. [12] Abuznait, A.H., Cain. C., Ingram, D., Burk, D. and Kaddoumi, A. (2011) Up-regulation of p-glycoprotein reduces intracellular accumulation of beta amyloid: Investigation of p-glycoprotein as a novel therapeutic target for Alzheimer’s disease. Journal of Pharmacy and Pharmacology, 63, 1111-1118. doi:10.1111/j.2042-7158.2011.01309.x [13] Kothandan, G., Gadhe, C.G., Madhavan, T., Choi, C.H. and Cho, S.J. (2011) Docking and 3D-QSAR (quantitative structure activity relationship) studies of flavones, the potent inhibitors of p-glycoprotein targeting the nucleotide binding domain. European Journal of Medicinal Chemistry, 46, 4078-4088. doi:10.1016/j.ejmech.2011.06.008 [14] Hartz, A.M., Miller, D.S. and Bauer, B. (2010) Restoring blood-brain barrier p-glycoprotein reduces brain amyloid-beta in a mouse model of Alzheimer’s disease. Molecular Pharmacology, 77, 715-723. doi:10.1124/mol.109.061754 [15] Jabeen, I., Pleban, K., Rinner, U., Chiba, P. and Ecker, G.F. (2012) Structure-activity relationships, ligand efficiency, and lipophilic efficiency profiles of benzophenone-type inhibitors of the multidrug transporter p-glycoprotein. Journal of Medicinal Chemistry, 55, 3261-3273. [16] Stouch, T.R. and Gudmundsson, O. (2002) Progress in understanding the structure-activity relationships of pglycoprotein. Advanced Drug Delivery Reviews, 54, 315-328. doi:10.1016/S0169-409X(02)00006-6 [17] Sharom, F.J. (1997) The p-glycoprotein efflux pump: How does it transport drugs? The Journal of Membrane Biology, 160, 161-175. doi:10.1007/s002329900305 [18] Li, Y., Wang, Y.H., Yang, L., Zhang, S.W., Liu, C.H. and Yang, S.L. (2005) Comparison of steroid substrates and inhibitors of p-glycoprotein by 3D-QSAR analysis. Journal of Molecular Structure, 733, 111-118. [19] Wang, R.B., Kuo, C.L., Lien, L.L. and Lien, E.J. (2003) Structure-activity relationship: Analyses of p-glycoprotein substrates and inhibitors. Journal of Clinical Pharmacy and Therapeutics, 28, 203-228. [20] Wang, Y.H., Li, Y., Yang, S.L. and Yang, L. (2005) An in silico approach for screening flavonoids as p-glycoprotein inhibitors based on a Bayesian-regularized neural network. Journal of Computer-Aided Molecular Design, 19, 137-147. doi:10.1007/s10822-005-3321-5 [21] Chen, C. and Yang, J. (2006) MI-QSAR models for prediction of corneal permeability of organic compounds. Acta Pharmacologica Sinica, 27, 193-204. doi:10.1111/j.1745-7254.2006.00241.x [22] Kubinyi, H. (1995) Strategies and recent technologies in drug discovery. Pharmazie, 50, 647-662. [23] Wiese, M. and Pajeva, I.K. (2001) Structure-activity relationships of multidrug resistance reversers. Current Medicinal Chemistry, 8, 685-713. [24] Taub, M.E., Podila, L., Ely, D. and Almeida, I. (2005) Functional assessment of multiple p-glycoprotein (p-gp) probe substrates: Influence of cell line and modulator concentration on p-gp activity. Drug Metabolism & Disposition, 33, 1679-1687. doi:10.1124/dmd.105.005421 [25] Alka, K. (2003) C-QSAR: A database of 18000 QSARs and associated biological and physical data. Journal of Computer-Aided Molecular Design, 17, 187-196. [26] Kuo, C.L., Assefa, H., Kamath, S., Brzozowski, Z., Slawinski, J., Saczewski, F., Buolamwini, J.K. and Neamati, N. (2004) Application of CoMFA and CoMSIA 3D-QSAR and docking studies in optimization of mercaptobenzenesulfonamides as HIV-1 integrase inhibitors. Journal of Medicinal Chemistry, 47, 385-399. doi:10.1021/jm030378i [27] Cramer, R.D., Patterson, D.E. and Bunce, J.D. (1988) Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. Journal of the American Chemical Society, 110, 5959-5967. [28] Chen, L.J., Lian, G.P. and Han, L.J. (2007) Prediction of human skin permeability using artificial neural network (ANN) modeling. Acta Pharmacologica Sinica, 28, 591-600. [29] Dhainaut, A., Regnier, G., Tizot, A., Pierre A., Leonce, S., Guilbaud, N., Kraus-Berthier, L. and Atassi, G. (1996) New purines and purine analogs as modulators of multidrug resistance. Journal of Medicinal Chemistry, 39, 4099-4108. [30] Ford, J.M., Bruggemann, E.P., Pastan, I., Gottesman, M.M. and Hait, W.N. (1990) Cellular and biochemical characterization of thioxanthenes for revesal of multidrug resistance in human and murine cell lines. Cancer Research, 50, 1748-1756. [31] Schmid, D., Ecker, G., Kopp, S., Hitzler, M. and Chiba, P. (1999) Structure-activity relationship studies of propafenone analogs cased on p-glycoprotein ATPase activity measurements. Biochemical Pharmacology, 58, 1447-1456. doi:10.1016/S0006-2952(99)00229-4 [32] Karelson, M. (2000) Molecular descriptors in QSAR/ QSPR. John Wiley & Sons, New York. [33] Karelson, M., Lobanov, V.S. and Katritzky, A.R. (1996) Quantum-chemical descriptors in QSAR/QSPR studies. Chemical Reviews, 96, 1027-1044. [34] Ponce, Y.M., Garit, J.A., Torrens, F., Zaldivar, V.R. and Castro, E.A. (2004) Atom, atom-type, and total linear indices of the “molecular pseudograph’s atom adjacency matrix”: Application to QSPR/QSAR studies of organic compounds. Molecules, 9, 1100-1123. doi:10.3390/91201100 [35] Iyer, M., Mishra, R., Han, Y. and Hopfinger, A.J. (2002) Predicting blood-brain barrier partitioning of organic molecules using membrane-interaction QSAR analysis. Pharmaceutical Research, 19, 1611-1621. doi:10.1023/A:1020792909928 [36] Abraham, M.H., Chadha, H.S. and Mitchell, R.C. (1995) Hydrogen bonding. 36. Determination of blood-brain barrier distribution using octanol-water partition coefficients. Drug Design and Discovery, 13, 123-131. [37] Abraham, M.H., Takacs-Novak, K. and Mitchell, R.C. (1997) On the partition of ampholytes: Application to blood-brain distribution. Journal of Pharmaceutical Sciences, 86, 310-315. doi:10.1021/js960328j [38] Bassolino-Klimas, D., Alper, H.E. and Stouch, T.R. (1993) Solute diffusion in lipid bilayer membranes: An atomic level study by molecular dynamics simulation. Biochemistry, 32, 12624-12637. doi:10.1021/bi00210a010 [39] Ma, X.L., Chen, C. and Yang, J. (2005) Predictive model of blood-brain barrier penetration of organic compounds. Acta Pharmacologica Sinica, 26, 500-512. doi:10.1111/j.1745-7254.2005.00068.x [40] Ohtsuki, S., Ito, S. and Terasaki, T. (2010) Is p-glycoprotein involved in amyloid-β elimination across the blood-brain barrier in Alzheimer’s disease? Clinical Pharmacology & Therapeutics, 88, 443-445. [41] Aller, S.G., Yu, J., Ward, A., Weng, Y., Chittaboina, S., Zhuo, R., Harrell, P.M., Trinh, Y.T., Zhang, Q., Urbatsch, I.L. and Chang, G. (2009) Structure of p-glycoprotein reveals a molecular basis for poly-specific drug binding. Science, 323, 1718-1722. doi:10.1126/science.1168750 [42] Ambudkar, S.V., Lelong, I.H., Zhang, J., Cardarelli, C.O., Gottesman, M.M. and Pastan, I. (1992) Partial purification and reconstitution of the human multidrug-resistance pump: Characterization of the drug-stimulatable ATP hydrolysis. Proceedings of the National Academy of Sciences of the United States of America, 89, 8472-8476. [43] Shapiro, A.B. and Ling, V. (1994) ATPase activity of purified and reconstituted p-glycoprotein from Chinese hamster ovary cells. The Journal of Biological Chemistry, 269, 3745-3754. [44] Doige, C.A., Yu, X. and Sharom, F.J. (1993) The effects of lipids and detergents on ATPase-active p-glycoprotein. Biochimica et Biophysica Acta, 1146, 65-72. [45] Litman, T., Zeuthen, T., Skovsgaard, T. and Stein, W.D. (1997) Structure-activity relationships of p-glycoprotein interacting drugs: Kinetic characterization of their effects on ATPase activity. Biochimica et Biophysica Acta, 1361, 159-168. [46] Waterhouse, R.N. (2003) Determination of lipophilicity and its use as a predictor of blood-brain barrier penetration of molecular imaging agents. Molecular Imaging & Biology, 5, 376-389. doi:10.1016/j.mibio.2003.09.014 [47] Palmeira, A., Sousa, E., Fernandes, M.X., Pinto, M.M. and Vasconcelos, M.H. (2012) Multidrug resistance reversal effects of aminated thioxanthones and interaction with cytochrome P450 3A4. Journal of Pharmacy and Pharmaceutical sciences, 15, 31-45. [48] Higgins, C.F. and Gottesman, M.M. (1992) Is the multidrug transporter a flippase? Trends in Biochemical Sciences, 17, 18-21. [49] Nazer, B., Hong, S. and Selkoe, D.J. (2008) LRP promotes endocytosis and degradation, but not transcytosis, of the amyloid-beta peptide in a blood-brain barrier in vitro model. Neurobiology of Disease, 30, 94-102. doi:10.1016/j.nbd.2007.12.005