An integrated computational study for screening medicinal plant phytochemicals for possible inhibitors of the human bile salt exporter pump

Authors

DOI:

https://doi.org/10.18203/2320-6012.ijrms20222372

Keywords:

BSEP, Molecular docking, Phytochemicals, MOE, ADMETsar

Abstract

Background: The primary carrier of bile acids in humans is the bile salt export pump (BSEP). which are crucial for the digestion and absorption of fat. Type 2 progressive familial intrahepatic cholestasis (PFIC-2), which is brought on when BSEP is suppressed and causes a decrease in bile flow and a buildup of cytotoxic bile salts in the liver, is one of the main causes of cholestasis in Saudi Arabia. Elucidate the inhibitory potential with minimal or no adverse effects.

Methods: The structure (6LR0) was downloaded from the PDB. Protein active sites were anticipated because these are pockets where ligands can bind and perform reactions to treat an infection. The PubChem zinc and mpd3 databases were used to get the ligands' structures. Molecular operating environment (MOE) was utilized to perform molecular docking of 1600 phytochemicals against BSEP. LigX was used to observe the docking hits for interaction analysis. 

Results: identification of 4 potential candidates for binding to the BSEP active site. then, Protox II-was used to forecast toxicity for the selected hits. Molecular dynamics simulations were also used to assess the binding complex's stability in water for 100 nanoseconds. The strong binding affinity of high-ranked drugs was predicted by our molecular docking and simulation.

Conclusions: This approach could be useful in determining the efficiency of a therapeutic molecule in the therapy of the BSEP. The aim of this research is to identify novel -BSEP drug targets, and in future in vitro and in vivo research could prove its clinical efficiency.

References

Kim SR, Saito Y, Itoda M, Maekawa K, Kawamoto M, Kamatani N et al. Genetic variations of the ABC transporter gene ABCB11 encoding the human bile salt export pump (BSEP) in a Japanese population. Drug Metab Pharmacokinet. 2009;24(3):277-81.

Glavinas H, Krajcsi P, Cserepes J, Sarkadi B. The role of ABC transporters in drug resistance, metabolism and toxicity. Curr Drug Deliv. 2004;1(1):27-42.

Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X, Dahlin A et al., Membrane transporters in drug development. Nat Rev Drug Discov. 2010;9(3):215-36.

Hofmann AF, Borgström B. The intraluminal phase of fat digestion in man: the lipid content of the micellar and oil phases of intestinal content obtained during fat digestion and absorption. J Clin Investig. 1964;43(2):247-57.

Fiorucci S, Mencarelli A, Palladino G, Cipriani S. Bile-acid-activated receptors: targeting TGR5 and farnesoid-X-receptor in lipid and glucose disorders. Trends Pharmacol Sci. 2009;30(11):570-80.

Kuipers F, Groen AK. Chipping away at gallstones. Nat Med. 2008;14(7):715-6.

Strautnieks SS, Byrne JA, Pawlikowska L, Thompson RJ. Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families. Gastroenterology. 2008;134(4):1203-14.

Perez MJ, Briz O. Bile-acid-induced cell injury and protection. World J Gastroenterol. 2009;15(14):1677-89.

Amer, S. and A. Hajira, A comprehensive review of progressive familial intrahepatic cholestasis (PFIC): genetic disorders of hepatocanalicular transporters. Gastroenterol Res. 2014;7(2):39.

Alonso EM, Snover DC, Montag A. Histologic pathology of the liver in progressive familial intrahepatic cholestasis. J Pediatric Gastroenterol Nutri. 2005;18(2):128-33.

Jansen P, Müller M. The molecular genetics of familial intrahepatic cholestasis. Gut. 2000;47(1):1-5.

Procko E, O'Mara ML, Bennett WF, Tieleman. The mechanism of ABC transporters: general lessons from structural and functional studies of an antigenic peptide transporter. FASEB J. 2015;23(5):1287-302.

Sussman JL, Lin D, Jiang J, Manning M. Protein Data Bank (PDB): database of three-dimensional structural information of biological macromolecules. Acta crystallographica. Section D, Biological crystallography. 2018;54(Pt 6 Pt 1):1078-84.

Vilar SG, Moro S. Medicinal chemistry and molecular operating environment (MOE): application of QSAR and molecular docking to drug discovery. Curr Top Med Chem. 2008;8(18):1555-72.

Kim S, Thiessen PA, Bolton EE, Chen J, Fu G, Gindulyte A et al. PubChem Substance and Compound databases. Nucleic Acids Res. 2016;44(D1):D1202-13.

Ashfaq UA, Mumtaz A, Qamar TU, Fatima T. MAPS Database: Medicinal plant Activities, Phytochemical and Structural Database. Bioinformation. 2013;9(19):993-5.

Irwin JJ, Shoichet BK. ZINC-is a free database of commercially available compounds for virtual screening. J Chem Info Modeling. 2005;45(1):177-82.

Mills N. ChemDraw Ultra 10.0 CambridgeSoft, 100 CambridgePark Drive, Cambridge, MA 02140. www. cambridgesoft. com. Commercial Price: 1910fordownload, 2150 for CD-ROM; Academic Price: 710fordownload, 800 for CD-ROM. ACS publication. 2006.

ARCHONTIS G, CHARMM: The Biomolecular Simulation Program. 2009.

Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001;46(1-3):3-26.

Sastry GM, Adzhigirey M, Day T, Annabhimoju R, Sherman W. Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J Comput Aided Mol Des. 2013;27(3):221-34.

Sonoki T, Obi T, Kubota S, Higashi M, Masai E, Katayama Y. Coexistence of two different O demethylation systems in lignin metabolism by Sphingomonas paucimobilis SYK-6: cloning and sequencing of the lignin biphenyl-specific O-demethylase (LigX) gene. Appl Environ Microbiol. 2000;66(5):2125-32.

Studio D. Discovery Studio. Accelrys 2.1. 2008.

Case D. AMBER 10; University of California: San Francisco, 2008. Google Scholar There is no corresponding record for this reference, 2008.

Man VH, Wu X, He X, Xie XQ, Brooks BR, Wang J. Determination of van der Waals Parameters Using a Double Exponential Potential for Nonbonded Divalent Metal Cations in TIP3P Solvent. J Chem Theory Comput. 2021;17(2):1086-97.

Amin SA, Ghosh K, Gayen S, Jha T. Chemical-informatics approach to COVID-19 drug discovery: Monte Carlo based QSAR, virtual screening and molecular docking study of some in-house molecules as papain-like protease (PLpro) inhibitors. J Biomol Struct Dyn. 2021;39(13):4764-73.

Ngo ST, Quynh Anh Pham N, Thi Le L, Pham DH, Vu VV. Computational Determination of Potential Inhibitors of SARS-CoV-2 Main Protease. J Chem Inf Model. 2020;60(12):5771-80.

Kräutler VWF, Van G, Hünenberger P. A fast SHAKE algorithm to solve distance constraint equations for small molecules in molecular dynamics simulations. J Computational Chem. 2001;22(5):501-8.

Bussi G, Parrinello M. Accurate sampling using Langevin dynamics. Physical Review E. 2007;75(5):056707.

Bhowmik D, Nandi R, Jagadeesan R, Kumar N, Prakash A, Kumar D. Identification of potential inhibitors against SARS-CoV-2 by targeting proteins responsible for envelope formation and virion assembly using docking based virtual screening, and pharmacokinetics approaches. Infect Genet Evol. 2020 Oct;84:104451 .

Roe DR. Cheatham TEIII, PTRAJ, and CPPTRAJ: software for processing and analysis of molecular dynamics trajectory data. J Chem Theory Computation. 2013;9(7):3084-95.

Kouznetsova VL, Zhang A, Tatineni M, Miller MA, Tsigelny IF. Potential COVID-19 papain-like protease PLpro inhibitors: repurposing FDA-approved drugs. Peer J. 2020;8:e9965.

Alamri MA, Tahir Ul Qamar M, Afzal O, Alabbas AB, Riadi Y et al. Discovery of anti-MERS-CoV small covalent inhibitors through pharmacophore modeling, covalent docking and molecular dynamics simulation. J Mol Liq. 2021;330:115699.

Marroquin LD, Bonin PD, Keefer J, Schroeter T. Assessment of bile salt export pump (BSEP) inhibition in membrane vesicles using radioactive and lc/ms-based detection methods. Curr Protoc. Toxicol. 2017;71:14.14.1-20.

Lu X, Liu L, Shan W, Kong L, Chen N, Lou Y et al. The Role of the Sodium-taurocholate Co-transporting Polypeptide (NTCP) and Bile Salt Export Pump (BSEP) in Related Liver Disease. Curr Drug Metab. 2019;20(5):377-89.

Ellis JL, Bove KE, Schuetz EG, Leino D, Valencia CA, Schuetz JD et al. Zebrafish abcb11b mutant reveals strategies to restore bile excretion impaired by bile salt export pump deficiency. Hepatology. 2018;67(4):1531-45.

Alves RR, Rosa IM. Biodiversity, traditional medicine and public health: where do they meet? J Ethnobiol Ethnomed. 2007;3(1):1-9.

Muzammil A, Waqas M, Umar A, Sufyan M, Rehman A, Haider A et al. Anti-aging Natural Compounds and their Role in the Regulation of Metabolic Pathways Leading to Longevity. Mini Rev Med Chem. 2021;21(18):2630-56.

Terstappen GC. A Reggiani In silico research in drug discovery. Trends Pharmacol Sci. 2001;22(1):23-6.

Makhuvele R, Naidu K, Gbashi S, Thipe VC, Adebo OA, Njobeh PB. The use of plant extracts and their phytochemicals for control of toxigenic fungi and mycotoxins. Heliyon. 2020;6(10):e05291.

Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001;46(1-3):3-26.

Brito MA. Pharmacokinetic study with computational tools in the medicinal chemistry course. Braz J Pharmace Sci. 2011;47(4):797-805.

Tsaioun K, Bottlaender M, Mabondzo A; Alzheimer's Drug Discovery Foundation. ADDME--Avoiding Drug Development Mistakes Early: central nervous system drug discovery perspective. BMC Neurol. 2009;9(1):S1.

Guengerich FP. Cytochromes P450, drugs, and diseases. Molecular interventions, 2003. 3(4): p. 194.

Bibi Z. Role of cytochrome P450 in drug interactions. Nutri Metabol. 2008;5(1):27.

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Published

2022-09-27

How to Cite

Alshehri, D. B. (2022). An integrated computational study for screening medicinal plant phytochemicals for possible inhibitors of the human bile salt exporter pump. International Journal of Research in Medical Sciences, 10(10), 2072–2079. https://doi.org/10.18203/2320-6012.ijrms20222372

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Original Research Articles