Bioinformatic analysis of highly consumed phytochemicals as P-gp binders to overcome drug-resistance

Narges Rajaei , Ghazaleh Rahgouy, Nasrin Panahi , Nima Razzaghi-Asl

Abstract


Background and purpose: P-glycoprotein (P-gp) is an adenosine triphosphate (ATP)-dependent membrane efflux pump for protecting cells against xenobiotic compounds. Unfortunately, overexpressed P-gp in neoplastic cells prevents cell entry of numerous chemotherapeutic agents leading to multidrug resistance (MDR). MDR cells may be re-sensitized to chemotherapeutic drugs via P-gp inhibition/modulation. Side effects of synthetic P-gp inhibitors encouraged the development of natural products.

Experimental approach: Molecular docking and density functional theory (DFT) calculations were used as fast and accurate computational methods to explore a structure binding relationship of some dietary phytochemicals inside distinctive P-gp binding sites (modulatory/inhibitory). For this purpose, top-scored docked conformations were subjected to per-residue energy decomposition analysis in the B3LYP level of theory with a 6-31g (d, p) basis set by Gaussian98 package.

Findings/Results: Consecutive application of computational techniques revealed binding modes/affinities of nutritive phytochemicals within dominant binding sites of P-gp. Blind docking scores for best-ranked compounds were superior to verapamil and rhodamine-123. Pairwise amino acid decomposition of superior docked conformations revealed Tyr303 as an important P-gp binding residue. DFT-based induced polarization analysis revealed major electrostatic fluctuations at the atomistic level and confirmed larger effects for amino acids with energy-favored binding interactions. Conformational analysis exhibited that auraptene and 7,4',7'',4'''-tetra-O-methylamentoflavone might not necessarily interact to P-gp binding sites through minimum energy conformations.

Conclusion and implications: Although there are still many hurdles to overcome, obtained results may propose a few nutritive phytochemicals as potential P-gp binding agents. Moreover; top-scored derivatives may have the chance to exhibit tumor chemo-sensitizing effects.

  

 

Highlights

Nima Razzaghi-Asl : PubMed , Google Scholar


Keywords


Chemosensitizers; Molecular docking; Multidrug resistance; P-gp; Phytochemicals.

Full Text:

PDF

References


Szakács G, Váradi A, Ozvegy-Laczka C, Sarkadi B. The role of ABC transporters in drug absorption, distribution, metabolism, excretion and toxicity (ADME-Tox). Drug Discov Today. 2008; 13(9-10):379-393. DOI: 10.1016/j.drudis.2007.12.010.

Heming CP, Muriithi L, Macharia LW, Filho PN, Moura-Neto V, Aran V. P-glycoprotein and cancer: what do we currently know? Heliyon. 2022;8(10):e11171,1-9.DOI: 10.1016/j.heliyon.2022.e11171.

Mashayekhi SO, Sattari MR, Routledge PA. Evidence of active transport involvement in morphine transport via MDCKII and MDCK-PGP cell lines. Res Pharm Sci. 2010;5(2):99-106. PMID: 21589798.

Tinoush B, Shirdel I, Wink M. Phytochemicals: potential lead molecules for MDR reversal. Front Pharmacol. 2020;11:832,1-35. DOI: 10.3389/fphar.2020.00832.

Qian J, Xia M, Liu W, Li L, Yang J, Mei Y, et al. Glabridin resensitizes p-glycoprotein-overexpressing multidrug-resistant cancer cells to conventional chemotherapeutic agents. Eur J Pharmacol. 2019;852:231-243. DOI: 10.1016/j.ejphar.2019.04.002.

Marques SM, Šupolíková L, Molčanová L, Šmejkal K, Bednar D, Slaninová I. Screening of natural compounds as P-glycoprotein inhibitors against multidrug resistance. Biomedicines. 2021;9(4):357,1-22. DOI: 10.3390/biomedicines9040357.

Mesgari Abbasi M, Valizadeh H, Hamishehkar H, Zakeri Milani P. Inhibition of P-glycoprotein expression and function by anti-diabetic drugs gliczalide, metformin, and pioglitazone in vitro and in situ. Res Pharm Sci. 2016;11(3):177-186. PMID: 27499787.

Silva N, Salgueiro L, Fortuna A, Cavaleiro C. P-glycoprotein mediated efflux modulators of plant origin: a short review. Nat Prod Commun. 2016;11(5):699-704. PMID: 27319155.

Kim TH, Shin S, Yoo SD, Shin BS. Effects of phytochemical P-glycoprotein modulators on the pharmacokinetics and tissue distribution of doxorubicin in mice. Molecules. 2018;23(2):349,1-14. DOI: 10.3390/molecules23020349.

Mohana S, Ganesan M, Agilan B, Karthikeyan R, Srithar G, Beaulah Mary R, et al. Screening dietary flavonoids for the reversal of P-glycoprotein-mediated multidrug resistance in cancer. Mol BioSyst. 2016;12(8):2458-2470. DOI: 10.1039/c6mb00187d.

Kushwaha PP, Maurya SK, Singh A, Prajapati KS, Singh AK, Shuaib M, et al. Bulbine frutescens phytochemicals as novel ABC-transporter inhibitors: a molecular docking and molecular dynamics simulation study. J Cancer Metastasis. 2021;7:2,1-13. DOI: 10.20517/2394-4722.2020.92.

Ganesan M, Kanimozhi G, Pradhapsingh B, Khan HA, Alhomida AS, Ekhzaimy A, et al. Phytochemicals reverse P-glycoprotein mediated multidrug resistance via signal transduction pathways. Biomed Pharmacother. 2021;139:111632,1-10. DOI: 10.1016/j.biopha.2021.111632.

Pacheco PA, Louvandini H, Giglioti R, Wedy BCR, Ribeiro JC, Verissimo CJ, et al. Phytochemical modulation of P-Glycoprotein and its gene expression in an ivermectin-resistant Haemonchus contortus isolate in vitro. Vet Parasitol. 2022;305:109713. DOI: 10.1016/j.vetpar.2022.109713.

Lomovskaya O, Bostian KA. Practical applications and feasibility of efflux pump inhibitors in the clinic-a vision for applied use. Biochem Pharmacol. 2006:71(7):910-918.

DOI: 10.1016/j.bcp.2005.12.008.

Mora Lagares L, Novič M. Recent advances on P-glycoprotein (ABCB1) transporter modelling with in silico methods. Int J Mol Sci. 2022;23(23):14804. DOI: 10.3390/ijms232314804.

Mamizadeh R, Hosseinzadeh Z, Razzaghi-Asl N, Ramazani A. In silico analysis of a few dietary phytochemicals as potential tumor chemo-sensitizers. Struct Chem. 2018;29:1139-1151. DOI: 10.1007/s11224-018-1098-0.

Gontijo VS, Dos Santos MH, Viegas C Jr. Biological and chemical aspects of natural biflavonoids from plants: a brief review. Mini Rev Med Chem. 2017;17(10):834-862. DOI: 10.2174/1389557517666161104130026.

Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017;7:42717,1-13. DOI: 10.1038/srep42717.

Nicklisch SC, Rees SD, McGrath AP, Gökirmak T, Bonito LT, Vermeer LM, et al. Global marine pollutants inhibit P-glycoprotein: environmental levels, inhibitory effects, and cocrystal structure. Sci Adv. 2016;2(4):e1600001,1-12. DOI: 10.1126/sciadv.1600001.

Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, et al. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem. 2009;30(16):2785-2791. DOI: 10.1002/jcc.21256.

Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, et al. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem. 1998;19:1639-1662. DOI:10.1002/(SICI)1096-987X(19981115)19: 14<1639::AID-JCC10>3.0.CO;2-B.

Salentin S, Schreiber S, Haupt VJ, Adasme MF, Schroeder M. PLIP: fully automated protein-ligand interaction profiler. Nucleic Acids Res. 2015;43(W1):W443-W447. DOI: 10.1093/nar/gkv315.

Fogarasi G, Zhou X, Taylor PW, Pulay P. The calculation of ab initio molecular geometries: efficient optimization by natural internal coordinates and empirical correction by offset forces. J Am Chem Soc. 1992;114:8191-8201. DOI: 10.1021/ja00047a032.

Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, et al. Gaussian, Inc., Pittsburgh PA, USA;1998. Available from: https://gaussian.com/glossary/g98/.

Mulliken RS. Electronic population analysis on LCAO-MO molecular wave functions. J Chem Phys. 1955;23(10):2343-2346. DOI: 10.1063/1.1740588.

Shapiro AB, Ling V. Positively cooperative sites for drug transport by P-glycoprotein with distinct drug specificities. Eur J Biochem. 1997;250(1):130-137. DOI: 10.1111/j.1432-1033.1997.00130.x.

Ferreira RJ, Ferreira MJ, dos Santos DJ. Molecular docking characterizes substrate-binding sites and efflux modulation mechanisms within P-glycoprotein. J Chem Inf Model. 2013;53(7):1747-1760. DOI: 10.1021/ci400195v.

Takanaga H, Ohnishi A, Yamada S, Matsuo H, Morimoto S, Shoyama Y. Polymethoxylated flavones in orange juice are inhibitors of P-glycoprotein but not cytochrome P450 3A4. J Pharmacol Exp Ther. 2000;293(1):230-236. PMID: 10734174.

Nabekura T, Yamaki T, Kitagawa S. Effects of chemopreventive citrus phytochemicals on human P-glycoprotein and multidrug resistance protein 1. Eur J Pharmacol. 2008;600(1-3):45-49. DOI: 10.1016/j.ejphar.2008.10.025.

Cui J, Liu X, Chow LMC. Flavonoids as P-gp inhibitors: a systematic review of SARs. Curr Med Chem. 2019;26(25):4799-4831. DOI: 10.2174/0929867325666181001115225.

Bai J, Zhao S, Fan X, Chen Y, Zou X, Hu M, et al. Inhibitory effects of flavonoids on P-glycoprotein in vitro and in vivo: food/herb-drug interactions and structure-activity relationships. Toxicol Appl Pharmacol. 2019;369:49-59. DOI: 10.1016/j.taap.2019.02.010.

Aller SG, Yu J, Ward A, Weng Y, Chittaboina S, Zhuo R, et al. Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science. 2009;323(5922):1718-1722. DOI: 10.1126/science.1168750.

Miri R, Razzaghi-asl N, Mohammadi MK. QM study and conformational analysis of an isatin Schiff base as a potential cytotoxic agent. J Mol Model. 2013;19(2):727-735. DOI: 10.1007/s00894-012-1586-x.

Nabekura T, Kamiyama S, Kitagawa S. Effects of dietary chemopreventive phytochemicals on P-glycoprotein function. Biochem Biophys Res Commun. 2005;327(3):866-870. DOI: 10.1016/j.bbrc.2004.12.081


Refbacks

  • There are currently no refbacks.


Creative Commons LicenseThis work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.