Binding Mode Analysis of ABCA7 for the Prediction of Novel Alzheimer's Disease Therapeutics

Overview

Journal Comput Struct Biotechnol J

Specialty Biotechnology

Date 2022 Jan 3

PMID 34976306

Citations 7

Authors

Vigneshwaran Namasivayam

Katja Stefan

Jens Pahnke

Sven Marcel Stefan

Affiliations

Soon will be listed here.

Abstract

The adenosine-triphosphate-(ATP)-binding cassette (ABC) transporter ABCA7 is a genetic risk factor for Alzheimer's disease (AD). Defective ABCA7 promotes AD development and/or progression. Unfortunately, ABCA7 belongs to the group of 'under-studied' ABC transporters that cannot be addressed by small-molecules. However, such small-molecules would allow for the exploration of ABCA7 as pharmacological target for the development of new AD diagnostics and therapeutics. Pan-ABC transporter modulators inherit the potential to explore under-studied ABC transporters as novel pharmacological targets by potentially binding to the proposed 'multitarget binding site'. Using the recently reported cryogenic-electron microscopy (cryo-EM) structures of ABCA1 and ABCA4, a homology model of ABCA7 has been generated. A set of novel, diverse, and potent pan-ABC transporter inhibitors has been docked to this ABCA7 homology model for the discovery of the multitarget binding site. Subsequently, application of pharmacophore modelling identified the essential pharmacophore features of these compounds that may support the rational drug design of innovative diagnostics and therapeutics against AD.

Citing Articles

Medicinal polypharmacology-a scientific glossary of terminology and concepts.

Stefan S, Rafehi M Front Pharmacol. 2024; 15:1419110.

PMID: 39092220 PMC: 11292611. DOI: 10.3389/fphar.2024.1419110.

The ABC's of Alzheimer risk gene ABCA7.

Duchateau L, Wawrzyniak N, Sleegers K Alzheimers Dement. 2024; 20(5):3629-3648.

PMID: 38556850 PMC: 11095487. DOI: 10.1002/alz.13805.

Iron Overload in Brain: Transport Mismatches, Microbleeding Events, and How Nanochelating Therapies May Counteract Their Effects.

Ficiara E, Stura I, Vernone A, Silvagno F, Cavalli R, Guiot C Int J Mol Sci. 2024; 25(4).

PMID: 38397013 PMC: 10889007. DOI: 10.3390/ijms25042337.

Ensemble Machine Learning Approaches Based on Molecular Descriptors and Graph Convolutional Networks for Predicting the Efflux Activities of MDR1 and BCRP Transporters.

Adachi A, Yamashita T, Kanaya S, Kosugi Y AAPS J. 2023; 25(5):88.

PMID: 37700207 DOI: 10.1208/s12248-023-00853-y.

Indole Derivatives as New Structural Class of Potent and Antiproliferative Inhibitors of Monocarboxylate Transporter 1 (MCT1; SLC16A1).

Puri S, Stefan K, Khan S, Pahnke J, Stefan S, Juvale K J Med Chem. 2022; 66(1):657-676.

PMID: 36584238 PMC: 9841531. DOI: 10.1021/acs.jmedchem.2c01612.

References

Pedersen J, Matsson P, Bergstrom C, Hoogstraate J, Noren A, LeCluyse E . Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013; 136(2):328-43. PMC: 3858191. DOI: 10.1093/toxsci/kft197. View

Surguchev A, Surguchov A . ABCA7-A Member of the ABC Transporter Family in Healthy and Ailing Brain. Brain Sci. 2020; 10(2). PMC: 7071517. DOI: 10.3390/brainsci10020121. View

Liu F, Zhang Z, Csanady L, Gadsby D, Chen J . Molecular Structure of the Human CFTR Ion Channel. Cell. 2017; 169(1):85-95.e8. DOI: 10.1016/j.cell.2017.02.024. View

Pena-Solorzano D, Stark S, Konig B, Sierra C, Ochoa-Puentes C . ABCG2/BCRP: Specific and Nonspecific Modulators. Med Res Rev. 2016; 37(5):987-1050. DOI: 10.1002/med.21428. View

Pasello M, Giudice A, Scotlandi K . The ABC subfamily A transporters: Multifaceted players with incipient potentialities in cancer. Semin Cancer Biol. 2019; 60:57-71. DOI: 10.1016/j.semcancer.2019.10.004. View

Beretta G, Cassinelli G, Pennati M, Zuco V, Gatti L . Overcoming ABC transporter-mediated multidrug resistance: The dual role of tyrosine kinase inhibitors as multitargeting agents. Eur J Med Chem. 2017; 142:271-289. DOI: 10.1016/j.ejmech.2017.07.062. View

Gameiro M, Silva R, Rocha-Pereira C, Carmo H, Carvalho F, Bastos M . Cellular Models and In Vitro Assays for the Screening of modulators of P-gp, MRP1 and BCRP. Molecules. 2017; 22(4). PMC: 6153761. DOI: 10.3390/molecules22040600. View

Saito H, Toyoda Y, Hirata H, Ota-Kontani A, Tsuchiya Y, Takada T . Soy Isoflavone Genistein Inhibits an Axillary Osmidrosis Risk Factor ABCC11: In Vitro Screening and Fractional Approach for ABCC11-Inhibitory Activities in Plant Extracts and Dietary Flavonoids. Nutrients. 2020; 12(8). PMC: 7468911. DOI: 10.3390/nu12082452. View

Saeed M, Boulos J, Elhaboub G, Rigano D, Saab A, Loizzo M . Cytotoxicity of cucurbitacin E from Citrullus colocynthis against multidrug-resistant cancer cells. Phytomedicine. 2019; 62:152945. DOI: 10.1016/j.phymed.2019.152945. View

10.

Silbermann K, Stefan S, Elshawadfy R, Namasivayam V, Wiese M . Identification of Thienopyrimidine Scaffold as an Inhibitor of the ABC Transport Protein ABCC1 (MRP1) and Related Transporters Using a Combined Virtual Screening Approach. J Med Chem. 2019; 62(9):4383-4400. DOI: 10.1021/acs.jmedchem.8b01821. View

11.

Zelcer N, Saeki T, Reid G, Beijnen J, Borst P . Characterization of drug transport by the human multidrug resistance protein 3 (ABCC3). J Biol Chem. 2001; 276(49):46400-7. DOI: 10.1074/jbc.M107041200. View

12.

Zhou Y, Hopper-Borge E, Shen T, Huang X, Shi Z, Kuang Y . Cepharanthine is a potent reversal agent for MRP7(ABCC10)-mediated multidrug resistance. Biochem Pharmacol. 2009; 77(6):993-1001. DOI: 10.1016/j.bcp.2008.12.005. View

13.

Pahnke J, Langer O, Krohn M . Alzheimer's and ABC transporters--new opportunities for diagnostics and treatment. Neurobiol Dis. 2014; 72 Pt A:54-60. PMC: 4199932. DOI: 10.1016/j.nbd.2014.04.001. View

14.

Wu C, Calcagno A, Hladky S, Ambudkar S, Barrand M . Modulatory effects of plant phenols on human multidrug-resistance proteins 1, 4 and 5 (ABCC1, 4 and 5). FEBS J. 2005; 272(18):4725-40. PMC: 1350838. DOI: 10.1111/j.1742-4658.2005.04888.x. View

15.

Oswald C, Holland I, Schmitt L . The motor domains of ABC-transporters. What can structures tell us?. Naunyn Schmiedebergs Arch Pharmacol. 2006; 372(6):385-99. DOI: 10.1007/s00210-005-0031-4. View

16.

Wu A, Wojtowicz K, Savary S, Hamon Y, Trombik T . Do ABC transporters regulate plasma membrane organization?. Cell Mol Biol Lett. 2020; 25:37. PMC: 7336681. DOI: 10.1186/s11658-020-00224-x. View

17.

Namanja H, Emmert D, Hrycyna C, Chmielewski J . Homodimers of the Antiviral Abacavir as Modulators of P-glycoprotein Transport in Cell Culture: Probing Tether Length. Medchemcomm. 2013; 4(10). PMC: 3833348. DOI: 10.1039/C3MD00196B. View

18.

Dhainaut A, REGNIER G, Tizot A, Pierre A, Leonce S, Guilbaud N . New purines and purine analogs as modulators of multidrug resistance. J Med Chem. 1996; 39(20):4099-108. DOI: 10.1021/jm960361i. View

19.

Yeh H, Qiu L, Sohma Y, Conrath K, Zou X, Hwang T . Identifying the molecular target sites for CFTR potentiators GLPG1837 and VX-770. J Gen Physiol. 2019; 151(7):912-928. PMC: 6605684. DOI: 10.1085/jgp.201912360. View

20.

Wang H, Tang Y, Wang L, Long C, Zhang Y . ATP-sensitive potassium channel openers and 2,3-dimethyl-2-butylamine derivatives. Curr Med Chem. 2007; 14(2):133-55. DOI: 10.2174/092986707779313390. View