Ligand-Based Pharmacophore Modeling and Virtual Screening to Discover Novel CYP1A1 Inhibitors

Author(s): Rana Adnan Tahir, Farwa Hassan, Abdul Kareem, Umer Iftikhar, Sheikh Arslan Sehgal*

Journal Name: Current Topics in Medicinal Chemistry

Volume 19 , Issue 30 , 2019

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Abstract:

Backgound: Cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) is an imperative enzyme due to its immersion in the biotransformation of a wide range of drugs and other xenobiotics. The involvement of enzymes in drug metabolism indicates an effective drug target for the development of novel therapeutics. The discovery of CYP1A1 specific inhibitors would be of particular relevance for the clinical pharmacology.

Methods: In the current work, in silico approaches were utilized to identify the novel potential compounds through a diverse set of reported inhibitors against CYP1A1. A dataset of reported compounds against CYP1 belongs to 10 different classes (alkaloids, coumarins, flavonoids, natural compounds, synthetic inhibitors, drugs, MBI’s, PAHs, naphthoquinone and stilbenoids) was retrieved and utilized for the comparative molecular docking analyses followed by pharmacophore modeling. The total eleven novel compounds were scrutinized on the basis of the highest binding affinities and least binding energy values.

Results: ZINC08792486 compound attained the highest gold fitness score of 90.11 against CYP1A1 among all the scrutinized molecules.

Conclusion: It has been elucidated that the residues Phe-224, Gly-316 and Ala-317 were conserved in all ligand-receptor interactions and critical for the development of effective therapies. The ADMET property analyses also predict better absorption and distribution of the selected hits that may be used in the future for in vitro validations and drug development.

Keywords: Cytochromes P450, CYP1A1, Molecular Docking, Pharmacophore, Virtual Screening, ADMET, Bioinformatics.

[1]
Yengi, L.G.; Xiang, Q.; Pan, J.; Scatina, J.; Kao, J.; Ball, S.E.; Fruncillo, R.; Ferron, G.; Roland Wolf, C. Quantitation of cytochrome P450 mRNA levels in human skin. Anal. Biochem., 2003, 316(1), 103-110.
[http://dx.doi.org/10.1016/S0003-2697(03)00042-3] [PMID: 12694732]
[2]
Nishimura, M.; Yaguti, H.; Yoshitsugu, H.; Naito, S.; Satoh, T. Tissue distribution of mRNA expression of human cytochrome P450 isoforms assessed by high-sensitivity real-time reverse transcription PCR. Yakugaku Zasshi, 2003, 123(5), 369-375.
[http://dx.doi.org/10.1248/yakushi.123.369] [PMID: 12772594]
[3]
van de Kerkhof, E.G.; de Graaf, I.A.; Ungell, A.L.; Groothuis, G.M. Induction of metabolism and transport in human intestine: validation of precision-cut slices as a tool to study induction of drug metabolism in human intestine in vitro. Drug Metab. Dispos., 2008, 36(3), 604-613.
[http://dx.doi.org/10.1124/dmd.107.018820] [PMID: 18094037]
[4]
Danielson, P.B. The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans. Curr. Drug Metab., 2002, 3(6), 561-597.
[http://dx.doi.org/10.2174/1389200023337054] [PMID: 12369887]
[5]
Zuber, R.; Modrianský, M.; Dvorák, Z.; Rohovský, P.; Ulrichová, J.; Simánek, V.; Anzenbacher, P. Effect of silybin and its congeners on human liver microsomal cytochrome P450 activities. Phytother. Res., 2002, 16(7), 632-638.
[http://dx.doi.org/10.1002/ptr.1000] [PMID: 12410543]
[6]
Nelson, D.R. Cytochrome P450 protocols; Springer: Berlin, 2006, pp. 1-10.
[7]
Zanger, U.M.; Turpeinen, M.; Klein, K.; Schwab, M. Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Anal. Bioanal. Chem., 2008, 392(6), 1093-1108.
[http://dx.doi.org/10.1007/s00216-008-2291-6] [PMID: 18695978]
[8]
Liu, J.; Taylor, S.F.; Dupart, P.S.; Arnold, C.L.; Sridhar, J.; Jiang, Q.; Wang, Y.; Skripnikova, E.V.; Zhao, M.; Foroozesh, M. Pyranoflavones: a group of small-molecule probes for exploring the active site cavities of cytochrome P450 enzymes 1A1, 1A2, and 1B1. J. Med. Chem., 2013, 56(10), 4082-4092.
[http://dx.doi.org/10.1021/jm4003654] [PMID: 23600958]
[9]
Rendic, S.; Guengerich, F.P. Contributions of human enzymes in carcinogen metabolism. Chem. Res. Toxicol., 2012, 25(7), 1316-1383.
[http://dx.doi.org/10.1021/tx300132k] [PMID: 22531028]
[10]
Zhou, S-F.; Chan, E.; Zhou, Z.W.; Xue, C.C.; Lai, X.; Duan, W. Insights into the structure, function, and regulation of human cytochrome P450 1A2. Curr. Drug Metab., 2009, 10(7), 713-729.
[http://dx.doi.org/10.2174/138920009789895552] [PMID: 19702529]
[11]
Walsh, A.A.; Szklarz, G.D.; Scott, E.E. Human cytochrome P450 1A1 structure and utility in understanding drug and xenobiotic metabolism. J. Biol. Chem., 2013, 288(18), 12932-12943.
[http://dx.doi.org/10.1074/jbc.M113.452953] [PMID: 23508959]
[12]
Androutsopoulos, V.P.; Tsatsakis, A.M.; Spandidos, D.A. Cytochrome P450 CYP1A1: wider roles in cancer progression and prevention. BMC Cancer, 2009, 9, 187.
[http://dx.doi.org/10.1186/1471-2407-9-187] [PMID: 19531241]
[13]
Hankinson, O. The aryl hydrocarbon receptor complex. Annu. Rev. Pharmacol. Toxicol., 1995, 35, 307-340.
[http://dx.doi.org/10.1146/annurev.pa.35.040195.001515] [PMID: 7598497]
[14]
Leong, C.O.; Gaskell, M.; Martin, E.A.; Heydon, R.T.; Farmer, P.B.; Bibby, M.C.; Cooper, P.A.; Double, J.A.; Bradshaw, T.D.; Stevens, M.F. Antitumour 2-(4-aminophenyl)benzothiazoles generate DNA adducts in sensitive tumour cells in vitro and in vivo. Br. J. Cancer, 2003, 88(3), 470-477.
[http://dx.doi.org/10.1038/sj.bjc.6600719] [PMID: 12569393]
[15]
Szklarz, G.D.; Paulsen, M.D. Molecular modeling of cytochrome P450 1A1: enzyme-substrate interactions and substrate binding affinities. J. Biomol. Struct. Dyn., 2002, 20(2), 155-162.
[http://dx.doi.org/10.1080/07391102.2002.10506831] [PMID: 12354067]
[16]
Sehgal, S.A. Pharmacoinformatics, adaptive evolution, and elucidation of six novel compounds for schizophrenia treatment by targeting DAOA (G72) isoforms. BioMed Res. Int., 2017, 2017(6), 1-19.
[http://dx.doi.org/10.1155/2017/5925714]
[17]
Sehgal, S.A. Pharmacoinformatics and molecular docking studies reveal potential novel Proline Dehydrogenase (PRODH) compounds for Schizophrenia inhibition. Med. Chem. Res., 2017, 26(2), 314-326.
[http://dx.doi.org/10.1007/s00044-016-1752-2]
[18]
Sehgal, S.A.; Mannan, S.; Kanwal, S.; Naveed, I.; Mir, A. Adaptive evolution and elucidating the potential inhibitor against schizophrenia to target DAOA (G72) isoforms. Drug Des. Devel. Ther., 2015, 9, 3471-3480.
[PMID: 26170631]
[19]
Tahir, R.A.; Wu, H.; Javed, N.; Khalique, A.; Khan, S.A.F.; Mir, A.; Ahmed, M.S.; Barreto, G.E.; Qing, H.; Ashraf, G.M.; Sehgal, S.A. Pharmacoinformatics and molecular docking reveal potential drug candidates against Schizophrenia to target TAAR6. J. Cell. Physiol., 2018.
[PMID: 30569503]
[20]
Tahir, R.A.; Sehgal, S.A. Pharmacoinformatics and molecular docking studies reveal potential novel compounds against schizophrenia by target SYN II. Comb. Chem. High Throughput Screen., 2018, 21(3), 175-181.
[http://dx.doi.org/10.2174/1386207321666180213092018] [PMID: 29436999]
[21]
Kanwal, S.; Jamil, F.; Ali, A.; Sehgal, S.A. Comparative modeling, molecular docking, and revealing of potential binding pockets of RASSF2; a candidate cancer gene. Interdiscip. Sci., 2017, 9(2), 214-223.
[http://dx.doi.org/10.1007/s12539-016-0145-z] [PMID: 26782783]
[22]
Tahir, R.A.; Sehgal, S.A.; Khattak, N.A.; Khan Khattak, J.Z.; Mir, A. Tumor necrosis factor receptor superfamily 10B (TNFRSF10B): an insight from structure modeling to virtual screening for designing drug against head and neck cancer. Theor. Biol. Med. Model., 2013, 10(1), 38.
[http://dx.doi.org/10.1186/1742-4682-10-38] [PMID: 23724937]
[23]
Berman, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T.N.; Weissig, H.; Shindyalov, I.N.; Bourne, P.E. The protein data bank. Nucleic Acids Res., 2000, 28(1), 235-242.
[http://dx.doi.org/10.1093/nar/28.1.235] [PMID: 10592235]
[24]
Sehgal, S.A.; Mirza, A.H.; Tahir, R.A.; Mir, A. Quick Guideline for Computational Drug Design; Bentham Science Publishers: Sharjah, 2018.
[http://dx.doi.org/10.2174/97816810860331180101]
[25]
Pettersen, E.F.; Goddard, T.D.; Huang, C.C.; Couch, G.S.; Greenblatt, D.M.; Meng, E.C.; Ferrin, T.E. UCSF Chimera--a visualization system for exploratory research and analysis. J. Comput. Chem., 2004, 25(13), 1605-1612.
[http://dx.doi.org/10.1002/jcc.20084] [PMID: 15264254]
[26]
Liu, J.; Sridhar, J.; Foroozesh, M. Cytochrome P450 family 1 inhibitors and structure-activity relationships. Molecules, 2013, 18(12), 14470-14495.
[http://dx.doi.org/10.3390/molecules181214470] [PMID: 24287985]
[27]
Mendelsohn, L.D. ChemDraw 8 ultra, windows and macintosh versions. J. Chem. Inf. Comput. Sci., 2004, 44(6), 2225-2226.
[http://dx.doi.org/10.1021/ci040123t]
[28]
Ultra, C. 6.0 and Chem3D Ultra; Cambridge Soft Corporation: Cambridge, USA, 2001.
[29]
Wolber, G.; Langer, T. LigandScout: 3-D pharmacophores derived from protein-bound ligands and their use as virtual screening filters. J. Chem. Inf. Model., 2005, 45(1), 160-169.
[http://dx.doi.org/10.1021/ci049885e] [PMID: 15667141]
[30]
Irwin, J.J.; Sterling, T.; Mysinger, M.M.; Bolstad, E.S.; Coleman, R.G. ZINC: a free tool to discover chemistry for biology. J. Chem. Inf. Model., 2012, 52(7), 1757-1768.
[http://dx.doi.org/10.1021/ci3001277] [PMID: 22587354]
[31]
Jones, D.T.; Taylor, W.R.; Thornton, J.M. A new approach to protein fold recognition. Nature, 1992, 358(6381), 86-89.
[http://dx.doi.org/10.1038/358086a0] [PMID: 1614539]
[32]
Trott, O.; Olson, A.J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
[PMID: 19499576]
[33]
Kiss, R.; Sandor, M.; Szalai, F.A. A public web service for drug discovery. J. Cheminform., 2012, 4(S1), 17.
[http://dx.doi.org/10.1186/1758-2946-4-S1-P17]
[34]
Cheng, F.; Li, W.; Zhou, Y.; Shen, J.; Wu, Z.; Liu, G.; Lee, P.W.; Tang, Y. admetSAR: a comprehensive source and free tool for assessment of chemical ADMET properties. J. Chem. Inf. Model., 2012, 52(11), 3099-3105.
[35]
Bolton, E.E. Wang, Y.; Thiessen, P.A.; Bryant, S.H. Annual reports in computational chemistry; Elsevier: London, 2008, Vol. 4, pp. 217-241.
[36]
Sander, T.; Freyss, J.; von Korff, M.; Rufener, C. DataWarrior: an open-source program for chemistry aware data visualization and analysis. J. Chem. Inf. Model., 2015, 55(2), 460-473.
[http://dx.doi.org/10.1021/ci500588j] [PMID: 25558886]
[37]
He, L.; He, T.; Farrar, S.; Ji, L.; Liu, T.; Ma, X. Antioxidants Maintain cellular redox homeostasis by elimination of reactive oxygen species. Cell. Physiol. Biochem., 2017, 44(2), 532-553.
[http://dx.doi.org/10.1159/000485089]
[38]
Vrzal, R.; Zdarilová, A.; Ulrichová, J.; Bláha, L.; Giesy, J.P.; Dvorák, Z. Activation of the aryl hydrocarbon receptor by berberine in HepG2 and H4IIE cells: Biphasic effect on CYP1A1. Biochem. Pharmacol., 2005, 70(6), 925-936.
[http://dx.doi.org/10.1016/j.bcp.2005.06.016] [PMID: 16046213]
[39]
Tang, W.; Sanville, E.; Henkelman, G. A grid-based Bader analysis algorithm without lattice bias. J. Phys. Condens. Matter, 2009, 21(8)084204
[http://dx.doi.org/10.1088/0953-8984/21/8/084204] [PMID: 21817356]
[40]
Li, J.; Cao, B.; Liu, X.; Fu, X.; Xiong, Z.; Chen, L.; Sartor, O.; Dong, Y.; Zhang, H. Berberine suppresses androgen receptor signaling in prostate cancer. Mol. Cancer Ther., 2011, 10(8), 1346-1356.
[http://dx.doi.org/10.1158/1535-7163.MCT-10-0985] [PMID: 21613449]
[41]
Mathé, G.; Triana, K.; Pontiggia, P.; Blanquet, D.; Hallard, M.; Morette, C. Data of pre-clinical and early clinical trials of acriflavine and hydroxy-methyl-ellipticine reviewed, enriched by the experience of their use for 18 months to 6 years in combinations with other HIV1 virostatics. Biomed. Pharmacother., 1998, 52(9), 391-396.
[http://dx.doi.org/10.1016/S0753-3322(99)80007-9] [PMID: 9856286]
[42]
Ojala, T.; Valkealahti, K.; Oja, E.; Pietikäinen, M. Texture discrimination with multidimensional distributions of signed gray-level differences. Pattern Recognit., 2001, 34(3), 727-739.
[http://dx.doi.org/10.1016/S0031-3203(00)00010-8]
[43]
Stein, A.C.; Álvarez, S.; Avancini, C.; Zacchino, S.; von Poser, G. Antifungal activity of some coumarins obtained from species of Pterocaulon (Asteraceae). J. Ethnopharmacol., 2006, 107(1), 95-98.
[http://dx.doi.org/10.1016/j.jep.2006.02.009] [PMID: 16574360]
[44]
Pratt, J. Psychotropic drug tolerance and dependence: Common underlying mechanisms. The biological bases of drug tolerance and dependence, 1991, 2-28.
[45]
Bravo, L. Polyphenols: chemistry, dietary sources, metabolism, and nutritional significance. Nutr. Rev., 1998, 56(11), 317-333.
[http://dx.doi.org/10.1111/j.1753-4887.1998.tb01670.x] [PMID: 9838798]
[46]
Deschner, E.E.; Ruperto, J.; Wong, G.; Newmark, H.L. Quercetin and rutin as inhibitors of azoxymethanol-induced colonic neoplasia. Carcinogenesis, 1991, 12(7), 1193-1196.
[http://dx.doi.org/10.1093/carcin/12.7.1193] [PMID: 2070483]
[47]
McAnlis, G.T.; McEneny, J.; Pearce, J.; Young, I.S. Absorption and antioxidant effects of quercetin from onions, in man. Eur. J. Clin. Nutr., 1999, 53(2), 92-96.
[http://dx.doi.org/10.1038/sj.ejcn.1600682] [PMID: 10099940]
[48]
Folkman, J. Seminars in medicine of the beth Israel hospital, Boston. Clinical applications of research on angiogenesis. N. Engl. J. Med., 1995, 333(26), 1757-1763.
[http://dx.doi.org/10.1056/NEJM199512283332608] [PMID: 7491141]
[49]
Cao, R.; Zhang, Y. The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3. Curr. Opin. Genet. Dev., 2004, 14(2), 155-164.
[http://dx.doi.org/10.1016/j.gde.2004.02.001] [PMID: 15196462]
[50]
Habu, Y.; Uchida, T.; Inui, T.; Nakashima, H.; Fukasawa, M.; Seki, S. Enhancement of the synthetic ligand-mediated function of liver NK1.1Ag+ T cells in mice by interleukin-12 pretreatment. Immunology, 2004, 113(1), 35-43.
[http://dx.doi.org/10.1111/j.1365-2567.2004.01932.x] [PMID: 15312134]
[51]
Kitade, M.; Yoshiji, H.; Kojima, H.; Ikenaka, Y.; Noguchi, R.; Kaji, K.; Yoshii, J.; Yanase, K.; Namisaki, T.; Asada, K.; Yamazaki, M.; Tsujimoto, T.; Akahane, T.; Uemura, M.; Fukui, H. Leptin-mediated neovascularization is a prerequisite for progression of nonalcoholic steatohepatitis in rats. Hepatology, 2006, 44(4), 983-991.
[http://dx.doi.org/10.1002/hep.21338] [PMID: 17006938]
[52]
Kapadia, S.R.; Oral, H.; Lee, J.; Nakano, M.; Taffet, G.E.; Mann, D.L. Hemodynamic regulation of tumor necrosis factor-α gene and protein expression in adult feline myocardium. Circ. Res., 1997, 81(2), 187-195.
[http://dx.doi.org/10.1161/01.RES.81.2.187] [PMID: 9242179]
[53]
Verma, R.P. Anti-cancer activities of 1, 4-naphthoquinones: a QSAR study. Anticancer. Agents Med. Chem., 2006, 6(5), 489-499.
[http://dx.doi.org/10.2174/187152006778226512]
[54]
Kerbel, R.S.; Kamen, B.A. The anti-angiogenic basis of metronomic chemotherapy. Nat. Rev. Cancer, 2004, 4(6), 423-436.
[http://dx.doi.org/10.1038/nrc1369] [PMID: 15170445]
[55]
Shimada, T.; Fujii-Kuriyama, Y. Metabolic activation of polycyclic aromatic hydrocarbons to carcinogens by cytochromes P450 1A1 and 1B1. Cancer Sci., 2004, 95(1), 1-6.
[http://dx.doi.org/10.1111/j.1349-7006.2004.tb03162.x] [PMID: 14720319]
[56]
Conney, A.H. Induction of microsomal enzymes by foreign chemicals and carcinogenesis by polycyclic aromatic hydrocarbons: G. H. A. Clowes Memorial Lecture. Cancer Res., 1982, 42(12), 4875-4917.
[PMID: 6814745]
[57]
Flora, K.; Hahn, M.; Rosen, H.; Benner, K. Milk thistle (Silybum marianum) for the therapy of liver disease. Am. J. Gastroenterol., 1998, 93(2), 139-143.
[http://dx.doi.org/10.1111/j.1572-0241.1998.00139.x] [PMID: 9468229]
[58]
Deininger, M.; Buchdunger, E.; Druker, B.J. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood, 2005, 105(7), 2640-2653.
[http://dx.doi.org/10.1182/blood-2004-08-3097] [PMID: 15618470]
[59]
Majsterek, I.; Sliwinski, T.; Poplawski, T.; Pytel, D.; Kowalski, M.; Slupianek, A.; Skorski, T.; Blasiak, J. Imatinib mesylate (STI571) abrogates the resistance to doxorubicin in human K562 chronic myeloid leukemia cells by inhibition of BCR/ABL kinase-mediated DNA repair. Mutat. Res., 2006, 603(1), 74-82.
[http://dx.doi.org/10.1016/j.mrgentox.2005.10.010] [PMID: 16388976]
[60]
Lee, S-K.; Kim, Y.; Kim, M.Y.; Kim, S.; Chun, Y-J. Potent inhibition of human cytochrome P450 1 enzymes by dimethoxyphenylvinyl thiophene. Arch. Pharm. Res., 2004, 27(2), 199-205.
[http://dx.doi.org/10.1007/BF02980107] [PMID: 15022723]
[61]
Sienkiewicz, P.; Ciolino, H.P.; Leslie, B.J.; Hergenrother, P.J.; Singletary, K.; Yeh, G.C. A novel synthetic analogue of a constituent of Isodon excisus inhibits transcription of CYP1A1, -1A2 and -1B1 by preventing activation of the aryl hydrocarbon receptor. Carcinogenesis, 2007, 28(5), 1052-1057.
[http://dx.doi.org/10.1093/carcin/bgl248] [PMID: 17183067]


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VOLUME: 19
ISSUE: 30
Year: 2019
Published on: 03 January, 2020
Page: [2782 - 2794]
Pages: 13
DOI: 10.2174/1568026619666191112104217
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