IN SILICO PHARMACOKINETICS AND MOLECULAR DOCKING OF THREE LEADS ISOLATED FROM TARCONANTHUS CAMPHORATUS L.

Authors

  • Amina I. Dirar
  • Ayman Y. Waddad
  • Magdi A. Mohamed Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Khartoum, Sudan
  • Malik S. Mohamed
  • Wadah J. Osman
  • Mona S. Mohammed
  • Mohamed A. A. Elbadawi
  • Sami Hamdoun

Keywords:

Hispidulin, Nepetin, Parthenolide, In silico pharmacokinetic, PharmMapper server and Auto-Dock 40 software

Abstract

Objective: To investigate the pharmacokinetic and toxicity profiles and spectrum of biological activities of three phytochemicals isolated from Tarconanthus camphoratus L.

Methods: Several integrated web based in silico pharmacokinetic tools were used to estimate the druggability of Hispidulin, Nepetin and Parthenolide. Afterward, the structural based virtual screening for the three compounds' potential targets was performed using PharmMapper online server. The molecular docking was conducted using Auto-Dock 4.0 software to study the binding interactions of these compounds with the targets predicted by PharmMapper server.

Results: The permeability properties for all compounds were found within the limit range stated for Lipinski׳s rule of five. Only Parthenolide proved to be able to penetrate through blood brain barrier. Isopentenyl-diphosphate delta-isomerase (IPPI), uridine-cytidine kinase-2 (UCK-2) and the mitogen-activated protein kinase kinase-1 (MEK-1) were proposed as potential targets for Hispidulin, Nepetin and Parthenolide, respectively. Nepetin and Parthenolide were predicted to have anticancer activities. The activity of Nepetin appeared to be mediated through UCK-2 inhibition. On the other hand, inhibition of MEK-1 and enhancement of TP53 expression were predicted as the anticancer mechanisms of Parthenolide. The three compounds showed interesting interactions and satisfactory binding energies when docked into their relevant targets.

Conclusion: The ADMET profiles and biological activity spectra of Hispidulin, Nepetin and Parthenolide have been addressed. These compounds are proposed to have activities against a variety of human aliments such as tumors, muscular dystrophy, and diabetic cataracts.

Keywords: Tarconanthus camphoratus L., Hispidulin, Nepetin, Parthenolide, In silico pharmacokinetic, Molecular docking, PharmMapper server, and Auto-Dock 4.0 software 

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References

Neamati N, Barchi JJ. New paradigms in drug design and discovery. Curr Top Med Chem 2002;2:1–73.

Sams-Dodd F. Drug discovery: selecting the optimal approach. Drug Discovery Today 2006;11:465–72.

Bharath EN, Manjula S, Vijaychand A. In silico drug design tool for overcoming the innovation deficit in the drug discovery process. Int J Pharm Pharm Sci 2011;3:8–12.

Moroy G, Martiny VY, Vayer P, Villoutreix BO, Miteva MA. Towards in silico structure-based ADMET prediction in drug discovery. Drug Discovery Today 2012:17;44–55.

Pelkonen O, Turpeinen M, Raunio H. In vivo-in vitro-in silico pharmacokinetic modelling in drug development: current status and future directions. Clin Pharmacokinet 2011;50:483–91.

Van de Waterbeemd H, Gifford E. ADMET in silico modelling: towards prediction paradise. Nat Rev Drug Discovery 2003:2;192–204.

Garneau-Tsodikova S. Special series: natural products at the core of drug discovery. Biopolymers 2010;93:753–4.

Petrovska BB. Historical review of medicinal plants' usage. Pharmacogn Rev 2012;6:1–5.

Mothana RAA, Gruenert R, Bednarski PJ, Lindequist U. Evaluation of the in vitro anticancer, antimicrobial and antioxidant activities of some Yemeni plants used in folk medicine. Pharmazie 2009;64:260–8.

Jamal W, Bari A, Mothana RA, Basudan O, Mohammed MS, Ng SW. Antimicrobial evaluation and crystal structure of Parthenolide from Tarconanthus camphoratus collected in Saudi Arabia. Asian J Chem 2014;26:5183–5.

Dirar AI, Mohamed MA, Osman B, Khalid HS, Ismail EMO, Mohamed MS. Pharmacological studies on four antitumor medicinal plants grown In Sudan. Int J Res Pharm Chem 2014;4:1004–8.

Dirar AI, Mohamed MA, Khalid HS, Osman B, Fadul E, Khalid A. In vitro antioxidant activity and phytochemical profiles of three antitumor medicinal plants grown In Sudan. World J Pharm Res 2014;3:136–42.

Dirar AI, Mohamed MA, Ahmed WJ, Mohammed MS, Khalid HS, Garelnabi EAE. Isolation and characterization of potential cytotoxic leads from Ambrosia maritima L. (Asteraceae). J Pharmacogn Phytochem 2014;3:38–41.

Osman WJA, Mothana RA, Basudan O, Mohammed MS, Mohamed MS. Antibacterial effect and radical scavenging activity of Hispidulin and Nepetin: A two flavones from Tarconanthus camphoratus L. World J Pharm Res 2014;4:424–33.

Molinspiration chemoinformatics, Novaulica, SK-900 26 Slovensky Grob, Slovak Republic; 1986.

Cheng F, Li W, Zhou Y, Shen J, Wu Z, Liu G, et al. admetSAR: a comprehensive source and free tool for assessment of chemical ADMET properties. J Chem Inf Model 2012;52:3099–105.

Carlsson L, Spjuth O, Adams S, Glen RC, Boyer S. Use of historic metabolic biotransformation data as a means of anticipating metabolic sites using MetaPrint2D and bio clips. BMC Bioinformatics 2010;11:362.

Poroikov VV, Filimonov DA, Ihlenfeldt WD, Gloriozova TA, Lagunin AA, Borodina YV, et al. Pass biological activity spectrum predictions in the enhanced open NCI database browser. J Chem Inf Comput Sci 2003;43:228–36.

O'Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR. Open babel: an open chemical toolbox. J Cheminf 2011;3:33.

Liu X, Ouyang S, Yu B, Liu Y, Huang K, Gong J, et al. Pharm mapper server: a web server for potential drug target identification using pharmacophore mapping approach. Nucleic Acids Res 2010;38:W609–14.

Guex N, Peitsch MC. SWISS-MODEL and the swiss-Pdb viewer: an environment for comparative protein modeling. Electrophoresis 1997;18:2714–23.

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;30:2785–91.

Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, et al. Automated docking using a Lamarckian genetic algorithm and empirical binding free energy function. J Comput Chem 1998;19:1639–62.

Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, et al. UCSF Chimera-a visualization system for exploratory research and analysis. J Comput Chem 2004; 25:1605–12.

Molecular Operating Environment (MOE), 2013.08; Chemical Computing Group Inc., 1010 Sherbooke St. West, Suit # 910, Montreal, QC, Canada, H3A 2R7; 2016.

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 Delivery Rev 2001;46:3–26.

Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD. Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 2002;45:2615–23.

Srimai V, Ramesh M, Parameshwar KS, Parthasarathy T. Computer-aided design of selective cytochrome P450 inhibitors and docking studies of alkylresorcinol derivatives. Med Chem Res 2013;22:5314–23.

Paramashivam SK, Elayaperumal K, Natarajan BB, Ramamoorthy MD, Balasubramanian S, Dhiraviam KN. In silico pharmacokinetic and molecular docking studies of small molecules derived from Indigofera aspalathoides Vahl targeting receptor tyrosine kinases. Bioinformation 2015;11:73–84.

Yang C, Li Q, Li Y. Targeting nuclear receptors with marine natural products. Mar Drugs 2014;12:601–35.

Amin ML. P-glycoprotein inhibition for optimal drug delivery. Drug Target Insights 2013;7:27–34.

Levin GM. P-glycoprotein: why this drug transporter may be clinically important. Curr Psychiatry 2012;11:38–40.

Ghosh D, Lo J, Morton D, Valette D, Xi J, Griswold J, et al. Novel aromatase inhibitors by structure-guided design. J Med Chem 2012;55:8464–76.

Lynch T, Price A. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician 2007;76:391–6.

Molowa DT, Andrew G, Shayne V, Guzelian PS. Purification and characterization of chlordecone reductase from human liver. J Biological Chem 1986;261:12624–7.

Multigner L, Kadhel P, Rouget F, Blanchet P, Cordier S. Chlordecone exposure and adverse effects in French west indies populations. Environ Sci Pollut Res 2016;23:3–8.

Hamm J, Tessanne K, Murphy CN, Prather RS. Transcriptional regulators TRIM28, SETDB1, and TP53 are aberrantly expressed in porcine embryos produced by in vitro fertilization in comparison to in vivo-and somatic-cell nuclear transfer-derived embryos. Mol Reprod Dev 2014;81:552–66.

Hahn FM, Hurlburt AP, Poulter CD. Escherichia coli open reading frame 696 is idi, a nonessential gene encoding isopentenyl diphosphate isomerase. J Bactriol 1999; 181:4499–504.

Wu Z, Wouters J, Poulter CD. Isopentenyl diphosphate isomerase. mechanism-based inhibition by diene analogues of isopentenyl diphosphate and dimethylallyl diphosphate. J Am Chem Soc 2005;127:17433–8.

Kemp LE, Bond CS, Hunter WN. Structure of 2C-methyl-d-erythritol 2,4-cyclodiphosphate synthase: an essential enzyme for isoprenoid biosynthesis and target for antimicrobial drug development. Proc Natl Acad Sci USA. 2002;99:6591–6.

Wouters J, Oudjama Y, Barkley SJ, Tricot C, Stalon V, Droogmans L, et al. Catalytic mechanism of Escherichia coli isopentenyl diphosphate

isomerase involves Cys-67, Glu-116, and Tyr-104 as suggested by

crystal structures of complexes with transition state analogues

and irreversible inhibitors. J Biol Chem 2003;14:11903–8.

Woulters J, Yin F, Song Y, Zhang Y, Oudjama Y, Stalon V, et al. Crystallographic investigation of phosphoantigen binding to isopentenyl pyrophosphate/dimethylallyl pyrophosphate isomerase. J Am Chem Soc 2005;127:536–7.

Eoh H, Brennan PJ, Crick DC. The Mycobacterium tuberculosis MEP (2C-methyl-D-erythritol 4-phosphate) pathway as a new drug target. Tuberculosis 2009;89:1–11.

Cosentino RO, Agüero F. Genetic profiling of the isoprenoid and sterol biosynthesis pathway genes of Trypanosoma cruzi. PLoS One 2014;9:1–16.

Houten SM, Wanders RJ, Waterham HR. Biochemical and genetic aspects of mevalonate kinase and its deficiency. Biochim Biophys Acta 2000;1529:19–32.

Suzuki NN, Koizumi K, Fukushima M, Matsuda A, Inagaki F. Structural basis for the specificity, catalysis and regulation of human uridine-cytidine kinase. Structure 2004;12:751–64.

Zlatopolskiy BD, Morgenroth A, Kunkel FH, Urusova EA, Dinger C, Kull T, et al. Synthesis and biologic study of IV-14, a new ribonucleoside radiotracer for tumor visualization. J Nucl Med 2009;50:1895–903.

Militão GC, Albuquerque MR, Pessoa OD, Pessoa C, Moraes ME, de Moraes MO, et al. Cytotoxic activity of nepetin, a flavonoid from eupatorium ballotaefolium HBK. Pharmazie 2004;59:965–6.

Ohren JF, Chen H, Pavlovsky A, Whitehead C, Zhang E, Kuffa P, et al. Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat Struct Mol Biol 2004;11:1192–7.

Gong R, Sun D, Zhong X, Sun Y, Li L. MEK1 expression and its relationship with clinical pathological features in hepatocellular carcinoma. Int J Clin Exp Med 2015;8:4087–93.

Parada-Turska J, Paduch R, Majdan M, Kandefer-Szerszeń M, Rzeski W. Antiproliferative activity of parthenolide against three human cancer cell lines and human umbilical vein endothelial cells. Pharmacol Rep 2007;59:233–7.

Published

01-05-2016

How to Cite

Dirar, A. I., A. Y. Waddad, M. A. Mohamed, M. S. Mohamed, W. J. Osman, M. S. Mohammed, M. A. A. Elbadawi, and S. Hamdoun. “IN SILICO PHARMACOKINETICS AND MOLECULAR DOCKING OF THREE LEADS ISOLATED FROM TARCONANTHUS CAMPHORATUS L”. International Journal of Pharmacy and Pharmaceutical Sciences, vol. 8, no. 5, May 2016, pp. 71-77, https://journals.innovareacademics.in/index.php/ijpps/article/view/10528.

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