Elucidating the binding specificity of interactive compounds targeting ATP-binding cassette subfamily G member 2 (ABCG2)
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Abstract
The ATP-binding cassette transporter superfamily plays a pivotal role in cellular detoxification and drug efflux. ATP-binding cassette subfamily G member 2 (ABCG2) referred to as the Breast cancer resistance protein has emerged as a key member involved in multidrug resistance displayed by cancer cells. Understanding the molecular basis of substrate and inhibitor recognition, and binding within the transmembrane domain of ABCG2 is crucial for the development of effective therapeutic strategies. Herein, utilizing state-of-the-art molecular docking algorithms and molecular dynamic (MD) simulations, molecular binding of substrates and inhibitors with ABCG2 are defined, distinctly. We performed extensive virtual screening of Drugbank to identify the potential candidates, and MD simulations of docked complexes were carried out in POPC lipid bilayer. Further, the binding affinities of compounds were estimated by free binding energy employing MM-GBSA. To gain deeper insight into the binding affinities and molecular characteristics contributing to inhibitory potential of certain substrates, we included some well-known inhibitors, like Imatinib, Tariquidar, and Ko 143, in our analysis. Docking results show three compounds, Docetaxel > Tariquidar > Tezacaftor having the highest binding affinities (≤ 12.00 kcal/mol) for ABCG2. Remarkably, MM-GBSA results suggest the most stable binding of Tariquidar with ABCG2 as compared to the other inhibitors. Furthermore, our results suggested that Docetaxel, Ozanimod, Pitavastatin, and Tezacaftor have the strongest affinity for the drug-binding site(s) of ABCG2. These results provide valuable insights into the key residues that may govern substrate/inhibitor recognition, shedding light on the molecular determinants influencing substrate specificity, transport kinetics, and ABCG2-mediated drug efflux.
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Cites
UCSF Chimera—A visualization system for exploratory research and analysis
Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C., & Ferrin, T. E. (2004) · Journal of Computational Chemistry · doi:10.1002/jcc.20084 · Cited by 45,260 · see citing works
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
The Amber biomolecular simulation programs
Case, D. A., Cheatham, T. E., Darden, T., Gohlke, H., Luo, R., Merz, K. M., Onufriev, A., Simmerling, C., Wang, B., & Woods, R. J. (2005) · Journal of Computational Chemistry · doi:10.1002/jcc.20290 · Cited by 9,535 · see citing works
LigPlot+: Multiple Ligand-Protein Interaction Diagrams for Drug Discovery
Laskowski, R., & Swindells, M. (2011) · Journal of Chemical Information and Modeling · doi:10.1021/ci200227u · Cited by 6,159 · see citing works
Sastry, G. M., Adzhigirey, M., Day, T., Annabhimoju, R., & Sherman, W. (2013) · Journal of Computer-Aided Molecular Design · doi:10.1007/s10822-013-9644-8 · Cited by 6,130 · see citing works
The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities
Genheden, S., & Ryde, U. (2015) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2015.1032936 · Cited by 5,636 · see citing works
Molecular Dynamics Simulation for All
Hollingsworth, S. A., & Dror, R. O. (2018) · Neuron · doi:10.1016/j.neuron.2018.08.011 · Cited by 3,359 · see citing works
Principles of early drug discovery
Hughes, J., Rees, S., Kalindjian, S., & Philpott, K. (2011) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.01127.x · Cited by 2,859 · see citing works
Radius of gyration as an indicator of protein structure compactness
Lobanov, M. Y., Bogatyreva, N. S., & Galzitskaya, O. V. (2008) · Molecular Biology · doi:10.1134/s0026893308040195 · Cited by 1,720 · see citing works
ABC transporters: the power to change
Rees, D. C., Johnson, E., & Lewinson, O. (2009) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2646 · Cited by 1,454 · see citing works
Molecular dynamics simulations: advances and applications
Gelpí, J. L., Hospital, A., Goñi, R., & Orozco, M. (2015) · Advances and Applications in Bioinformatics and Chemistry · doi:10.2147/aabc.s70333 · Cited by 951 · see citing works
Regulation of protein-ligand binding affinity by hydrogen bond pairing
Chen, D., Oezguen, N., Urvil, P., Ferguson, C. G., Dann, S. M., & Savidge, T. (2016) · Science Advances · doi:10.1126/sciadv.1501240 · Cited by 937 · see citing works
Methods of protein structure comparison
Kufareva, I., & Abagyan, R. (2012) · Methods in molecular biology · doi:10.1007/978-1-61779-588-6_10 · Cited by 625 · see citing works
[Radius of gyration is indicator of compactness of protein structure].
Lobanov, M. I., Bogatyreva, N. S., & Galzitskaia, O. V. (2008) · PubMed · Cited by 568 · see citing works
Molecular dynamics simulations and novel drug discovery
Liu, X., Shi, D., Zhou, S., Liu, H., Liu, H., & Yao, X. (2017) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2018.1403419 · Cited by 520 · see citing works
Structure of the human multidrug transporter ABCG2
Taylor, N. M. I., Manolaridis, I., Jackson, S. M., Kowal, J., Stahlberg, H., & Locher, K. P. (2017) · Nature · doi:10.1038/nature22345 · Cited by 418 · see citing works
Role of breast cancer resistance protein (BCRP/ABCG2) in cancer drug resistance
Natarajan, K., Xie, Y., Baer, M. R., & Ross, D. D. (2012) · Biochemical Pharmacology · doi:10.1016/j.bcp.2012.01.002 · Cited by 408 · see citing works
ABC Transporters in Cancer Stem Cells: Beyond Chemoresistance
Begicevic, R.-R., & Falasca, M. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18112362 · Cited by 399 · see citing works
Structural basis of small-molecule inhibition of human multidrug transporter ABCG2
Jackson, S. M., Manolaridis, I., Kowal, J., Zechner, M., Taylor, N. M. I., Bause, M., Bauer, S., Bartholomäus, R., Bernhardt, G., König, B., et al. (2018) · Nature Structural & Molecular Biology · doi:10.1038/s41594-018-0049-1 · Cited by 325 · see citing works
Houghton, P. J., Germain, G. S., Harwood, F. C., Schuetz, J. D., Stewart, C. F., Buchdunger, E., & Traxler, P. M. (2004) · Cancer Research · doi:10.1158/0008-5472.can-03-3344 · Cited by 323 · see citing works
Structural and functional diversity calls for a new classification of ABC transporters
Thomas, C., Aller, S. G., Beis, K., Carpenter, E. P., Chang, G. A., Chen, L., Dassa, E., Dean, M. C., Duong, F., Ekiert, D. C., et al. (2020) · FEBS Letters · doi:10.1002/1873-3468.13935 · Cited by 284 · see citing works
Involvement of BCRP (ABCG2) in the Biliary Excretion of Pitavastatin
Hirano, M., Maeda, K., Matsushima, S., Nozaki, Y., Kusuhara, H., & Sugiyama, Y. (2005) · Molecular Pharmacology · doi:10.1124/mol.105.014019 · Cited by 256 · see citing works
Molecular and cellular paradigms of multidrug resistance in cancer
Vaidya, F. U., Chhipa, A. S., Mishra, V., Gupta, V. K., Rawat, S. G., Kumar, A., & Pathak, C. (2020) · Cancer Reports · doi:10.1002/cnr2.1291 · Cited by 208 · see citing works
ABCG2 transports anticancer drugs via a closed-to-open switch
Orlando, B. J., & Liao, M. (2020) · Nature Communications · doi:10.1038/s41467-020-16155-2 · Cited by 198 · see citing works
Kannan, P., Telu, S., Shukla, S., Ambudkar, S. V., Pike, V. W., Halldin, C., Gottesman, M. M., Innis, R. B., & Hall, M. D. (2010) · ACS Chemical Neuroscience · doi:10.1021/cn100078a · Cited by 181 · see citing works
Elber, R., Ruymgaart, A. P., & Hess, B. (2011) · The European Physical Journal Special Topics · doi:10.1140/epjst/e2011-01525-9 · Cited by 166 · see citing works
The role of hydrogen-bonds in drug binding.
Wade, R. C., & Goodford, P. J. (1989) · PubMed · Cited by 151 · see citing works
Nakanishi, T., Shiozawa, K., Hassel, B. A., & Ross, D. D. (2006) · Blood · doi:10.1182/blood-2005-10-4020 · Cited by 148 · see citing works
The Inhibitor Ko143 Is Not Specific for ABCG2
Weidner, L. D., Zoghbi, S. S., Lu, S., Shukla, S., Ambudkar, S. V., Pike, V. W., Mulder, J., Gottesman, M. M., Innis, R. B., & Hall, M. D. (2015) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.115.225482 · Cited by 141 · see citing works
Ridley, K., & Condren, M. E. (2020) · The Journal of Pediatric Pharmacology and Therapeutics · doi:10.5863/1551-6776-25.3.192 · Cited by 117 · see citing works
Mishra, C. B., Pandey, P., Sharma, R. D., Malik, M. Z., Mongre, R. K., Lynn, A. M., Prasad, R., Jeon, R., & Prakash, A. (2020) · Briefings in Bioinformatics · doi:10.1093/bib/bbaa378 · Cited by 101 · see citing works
Self-citationA compression strategy for particle mesh Ewald theory
Simmonett, A. C., & Brooks, B. R. (2021) · The Journal of Chemical Physics · doi:10.1063/5.0040966 · Cited by 101 · see citing works
Structural Basis of Drug Recognition by the Multidrug Transporter ABCG2
Kowal, J., Ni, D., Jackson, S. M., Manolaridis, I., Stahlberg, H., & Locher, K. P. (2021) · Journal of Molecular Biology · doi:10.1016/j.jmb.2021.166980 · Cited by 82 · see citing works
Structures of ABCG2 under turnover conditions reveal a key step in the drug transport mechanism
Yu, Q., Ni, D., Kowal, J., Manolaridis, I., Jackson, S. M., Stahlberg, H., & Locher, K. P. (2021) · Nature Communications · doi:10.1038/s41467-021-24651-2 · Cited by 80 · see citing works
Khater, S., Kumar, P., Dasgupta, N., Das, G., Ray, S., & Prakash, A. (2021) · Frontiers in Microbiology · doi:10.3389/fmicb.2021.647693 · Cited by 66 · see citing works
Self-citationStructure-Based Functional Design of Drugs: From Target to Lead Compound
Anderson, A. C. (2011) · Methods in molecular biology · doi:10.1007/978-1-60327-216-2_23 · Cited by 53 · see citing works
Clinician’s Guide to Using Ozanimod for the Treatment of Ulcerative Colitis
Sands, B. E., Schreiber, S., Blumenstein, I., Chiorean, M. V., Ungaro, R. C., & Rubin, D. T. (2023) · Journal of Crohn s and Colitis · doi:10.1093/ecco-jcc/jjad112 · Cited by 50 · see citing works
Cree, B., Selmaj, K. W., Steinman, L., Comı, G., Bar‐Or, A., Arnold, D. L., Hartung, H., Montalbán, X., Havrdová, E., Sheffield, J. K., et al. (2022) · Multiple Sclerosis Journal · doi:10.1177/13524585221102584 · Cited by 50 · see citing works
Pitavastatin: A Review in Hypercholesterolemia
Hoy, S. M. (2017) · American Journal of Cardiovascular Drugs · doi:10.1007/s40256-017-0213-8 · Cited by 37 · see citing works
Elucidation of stable intermediates in urea-induced unfolding pathway of human carbonic anhydrase IX
Prakash, A., Dixit, G., Meena, N. K., Singh, R., Vishwakarma, P., Mishra, S., & Lynn, A. M. (2017) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2017.1355847 · Cited by 32 · see citing works
Self-citationGeorge, A., Mondal, S., Purnaprajna, M., & Athri, P. (2022) · ACS Omega · doi:10.1021/acsomega.2c03189 · Cited by 27 · see citing works
The Impact of Sphinogosine-1-Phosphate Receptor Modulators on COVID-19 and SARS-CoV-2 Vaccination
Baker, D., Forte, E., Pryce, G., Kang, A. S., James, L. K., Giovannoni, G., & Schmierer, K. (2022) · Multiple Sclerosis and Related Disorders · doi:10.1016/j.msard.2022.104425 · Cited by 25 · see citing works
Mikhailovskii, O., Izmailov, S. A., Xue, Y., Case, D. A., & Skrynnikov, N. R. (2023) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.3c01531 · Cited by 23 · see citing works
Banerjee, A., Pata, J., Chaptal, V., Boumendjel, A., Falson, P., & Prasad, R. (2023) · Drug Resistance Updates · doi:10.1016/j.drup.2023.100992 · Cited by 20 · see citing works
Self-citationDu, Q., Jiang, G., Li, S., Liu, Y., & Huang, Z. (2018) · Oncoscience · doi:10.18632/oncoscience.444 · Cited by 15 · see citing works
Kar, R. K., Kharerin, H., Padinhateeri, R., & Bhat, P. J. (2016) · Journal of Molecular Biology · doi:10.1016/j.jmb.2016.11.005 · Cited by 13 · see citing works
Structural Basis of the Allosteric Inhibition of Human ABCG2 by Nanobodies
Irobalieva, R. N., Manolaridis, I., Jackson, S. M., Ni, D., Pardon, E., Stahlberg, H., Steyaert, J., & Locher, K. P. (2023) · Journal of Molecular Biology · doi:10.1016/j.jmb.2023.168234 · Cited by 13 · see citing works
Arylcoumarin perturbs SARS-CoV-2 pathogenesis by targeting the S-protein/ACE2 interaction
Singh, R., Kumar, A., Rane, J. S., Khan, R., Tripathi, G., Ajay, A. K., Prakash, A., & Ray, S. (2022) · Scientific Reports · doi:10.1038/s41598-022-20759-7 · Cited by 11 · see citing works
Self-citationMacromolecular Structure Comparison and Docking: An Algorithmic Review
Paquet, E., & Viktor, H. L. (2013) · Current Pharmaceutical Design · doi:10.2174/1381612811319120006 · Cited by 9 · see citing works
Ramaswamy, A., Ostwal, V. S., Bose, S., Sirohi, B., Poladia, B. P., Sahu, A., BHARGAVA, P. G., Doshi, V., Dusane, R., Nashikkar, C., et al. (2018) · Indian Journal of Cancer · doi:10.4103/ijc.ijc_353_17 · Cited by 7 · see citing works
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Reversal of ABCG2-mediated drug resistance by tinodasertib (ETC-206)
Yang, H., Li, Z., Wu, Z., Chen, X., Bo, L., Patel, H., Zhang, B., Xiong, W., Wang, W., & Chen, Z. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1606857 · Cited by 4 · see citing works
- Authors
- Kumar, P., Kumari, I., Prasad, R., Ray, S., Banerjee, A., & Prakash, A.
- Affiliations
- Jawaharlal Nehru University (IN)
- Amity University (IN)
- Amity University Gurugram (IN)
- Mahatma Gandhi Central University (IN)
- Corresponding author
- Banerjee, Atanu
- Prakash, Amresh
- Venue
- Molecular Diversity
- Published
- 2025-01-09
- Volume
- 29
- Issue
- 6
- Pages
- 5635-5648
- ISSN
- 1381-1991 (ISSN-L)
- 1573-501X
- OpenAlex
- W4406219493
- Cited by
- 1
- References
- 50
- Citations by year
- 2025: 1
- FWCI
- 0.41
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Molecular Diversity (publishedVersion)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Interaction Studies and Fluorescence Analysis
- Keywords
- ABCG2, ABC transporters, substrate specificity, inhibitor binding, multidrug resistance, drug efflux, tariquidar, imatinib, docetaxel, tezacaftor, ozanimod, pitavastatin, binding affinity, POPC bilayer, MM-GBSA binding free energy, virtual screening
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily G, Member 2, Binding Sites, Humans, Neoplasm Proteins, Protein Binding, Molecular Dynamics Simulation, Molecular Docking Simulation
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