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Current Medicinal Chemistry

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ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

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General Research Article

Pharmacophore & QSAR Guided Design, Synthesis, Pharmacokinetics and In vitro Evaluation of Curcumin Analogs for Anticancer Activity

Author(s): Sarfaraz Alam, Surjeet Verma, Kaneez Fatima, Suaib Luqman, Santosh Kumar Srivastava and Feroz Khan*

Volume 31, Issue 5, 2024

Published on: 15 June, 2023

Page: [620 - 639] Pages: 20

DOI: 10.2174/0929867330666230428162720

Price: $65

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Abstract

Background: As a part of our discovery of plant-based lead molecules, we provide a helpful tool, which helps in identification, designing, optimising, structural modifications, and prediction of curcumin, to discover novel analogs with enhanced bioavailability, pharmacologically safe, and anticancer potential.

Methods: QSAR (Quantitative structure-activity relationship) and pharmacophore mapping models were developed and further used to design, synthesize, pharmacokinetics, and in vitro evaluation of curcumin analogs for anticancer activity.

Results: The QSAR model yielded a high activity-descriptors relationship accuracy (r2) of 84%, a high activity prediction accuracy (rcv2) of 81%, and external set prediction accuracy of 89%. The QSAR study indicates that the five chemical descriptors were significantly correlated with anticancer activity. The important pharmacophore features identified were a hydrogen bond acceptor, a hydrophobic centre, and a negative ionizable centre. The model's predictive ability was evaluated against a set of chemically synthesized curcumin analogs. Among the tested compounds, nine curcumin analogs were found with IC50 values of 0.10 to 1.86 μg/mL. The active analogs were assessed for pharmacokinetics compliance. EGFR was identified as a potential target of synthesized active curcumin analogs through docking studies.

Conclusion: Integrating in silico design, QSAR-driven virtual screening, chemical synthesis, and experimental in vitro evaluation may lead to the early discovery of novel and promising anticancer compounds from natural sources. The developed QSAR model and common pharmacophore generation were used as a designing and predictive tool to develop novel curcumin analogs. This study may help optimize the therapeutic relationships of studied compounds for further drug development and their potential safety concerns. This study may guide compound selection and designing novel active chemical scaffolds or new combinatorial libraries of the curcumin series.

Keywords: QSAR, pharmacophore, ADMET, curcumin, pharmacokinetics, anticancer, docking, drug design.

« Previous Next »
[1]
Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2021, 71(3), 209-249.
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[2]
Dikshit, R.; Gupta, P.C.; Ramasundarahettige, C.; Gajalakshmi, V.; Aleksandrowicz, L.; Badwe, R.; Kumar, R.; Roy, S.; Suraweera, W.; Bray, F.; Mallath, M.; Singh, P.K.; Sinha, D.N.; Shet, A.S.; Gelband, H.; Jha, P. Cancer mortality in India: A nationally representative survey. Lancet, 2012, 379(9828), 1807-1816.
[http://dx.doi.org/10.1016/S0140-6736(12)60358-4] [PMID: 22460346]
[3]
Kaur, R.; Kapoor, K.; Kaur, H. Plants as a source of anticancer agents. J. Nat. Prod. Plant Resour., 2011, 1, 119-124.
[4]
Chattopadhyay, I.; Biswas, K.; Bandyopadhyay, U.; Banerjee, R.K. Turmeric and curcumin: Biological actions and medicinal applications. Curr. Sci., 2004, 87, 44-53.
[5]
Ammon, H.; Wahl, M. Pharmacology of Curcuma longa. Planta Med., 1991, 57(1), 1-7.
[http://dx.doi.org/10.1055/s-2006-960004] [PMID: 2062949]
[6]
Kunnumakkara, A.B.; Anand, P.; Aggarwal, B.B. Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins. Cancer Lett., 2008, 269(2), 199-225.
[http://dx.doi.org/10.1016/j.canlet.2008.03.009] [PMID: 18479807]
[7]
Kuttan, R.; Bhanumathy, P.; Nirmala, K.; George, M.C. Potential anticancer activity of turmeric (Curcuma longa). Cancer Lett., 1985, 29(2), 197-202.
[http://dx.doi.org/10.1016/0304-3835(85)90159-4] [PMID: 4075289]
[8]
Aggarwal, B.B.; Sundaram, C.; Malani, N.; Ichikawa, H. Curcumin: The Indian solid gold. Adv. Exp. Med. Biol., 2007, 595, 1-75.
[http://dx.doi.org/10.1007/978-0-387-46401-5_1] [PMID: 17569205]
[9]
Kiso, Y.; Suzuki, Y.; Watanabe, N.; Oshima, Y.; Hikino, H. Antihepatotoxic principles of Curcuma longa rhizomes. Planta Med., 1983, 49(11), 185-187.
[http://dx.doi.org/10.1055/s-2007-969845] [PMID: 6657788]
[10]
Venkatesan, N.; Punithavathi, D.; Arumugam, V. Curcumin prevents adriamycin nephrotoxicity in rats. Br. J. Pharmacol., 2000, 129(2), 231-234.
[http://dx.doi.org/10.1038/sj.bjp.0703067] [PMID: 10694226]
[11]
Srivastava, R.; Dikshit, M.; Srimal, R.C.; Dhawan, B.N. Anti-thrombotic effect of curcumin. Thromb. Res., 1985, 40(3), 413-417.
[http://dx.doi.org/10.1016/0049-3848(85)90276-2] [PMID: 4082116]
[12]
Nirmala, C.; Puvanakrishnan, R. Protective role of curcumin against isoproterenol induced myocardial infarction in rats. Mol. Cell. Biochem., 1996, 159(2), 85-93.
[http://dx.doi.org/10.1007/BF00420910] [PMID: 8858558]
[13]
Mahady, G.B.; Pendland, S.L.; Yun, G.; Lu, Z.Z. Turmeric (Curcuma longa) and curcumin inhibit the growth of Helicobacter pylori, a group 1 carcinogen. Anticancer Res., 2002, 22(6C), 4179-4181.
[PMID: 12553052]
[14]
Ouassaf, M.; Daoui, O.; Alam, S.; Elkhattabi, S.; Belaidi, S.; Chtita, S. Pharmacophore-based virtual screening, molecular docking, and molecular dynamics studies for the discovery of novel FLT3 inhibitors. J. Biomol. Struct. Dyn., 2022, 1-13.
[http://dx.doi.org/10.1080/07391102.2022.2123403] [PMID: 36106982]
[15]
Alam, S.; Khan, F. 3D-QSAR, Docking, ADME/Tox studies on Flavone analogs reveal anticancer activity through Tankyrase inhibition. Sci. Rep., 2019, 9(1), 5414.
[http://dx.doi.org/10.1038/s41598-019-41984-7] [PMID: 30932078]
[16]
Jorgensen, W.L. The many roles of computation in drug discovery. Science, 2004, 303(5665), 1813-1818.
[http://dx.doi.org/10.1126/science.1096361] [PMID: 15031495]
[17]
Kalyaanamoorthy, S.; Chen, Y.P.P. Structure-based drug design to augment hit discovery. Drug Discov. Today, 2011, 16(17-18), 831-839.
[http://dx.doi.org/10.1016/j.drudis.2011.07.006] [PMID: 21810482]
[18]
Mendez, D.; Gaulton, A.; Bento, A.P.; Chambers, J.; De Veij, M.; Félix, E.; Magariños, M.P.; Mosquera, J.F.; Mutowo, P.; Nowotka, M.; Gordillo-Marañón, M.; Hunter, F.; Junco, L.; Mugumbate, G.; Rodriguez-Lopez, M.; Atkinson, F.; Bosc, N.; Radoux, C.J.; Segura-Cabrera, A.; Hersey, A.; Leach, A.R. ChEMBL: Towards direct deposition of bioassay data. Nucleic Acids Res., 2019, 47(D1), D930-D940.
[http://dx.doi.org/10.1093/nar/gky1075] [PMID: 30398643]
[19]
Sahu, N.K.; Bari, S.B.; Kohli, D.V. Molecular modeling studies of some substituted chalcone derivatives as cysteine protease inhibitors. Med. Chem. Res., 2012, 21(11), 3835-3847.
[http://dx.doi.org/10.1007/s00044-011-9900-1]
[20]
Alam, S.; Nasreen, S.; Ahmad, A.; Darokar, M.P.; Khan, F. Detection of natural inhibitors against human liver cancer cell lines through QSAR, molecular docking and ADMET studies. Curr. Top. Med. Chem., 2021, 21(8), 686-695.
[http://dx.doi.org/10.2174/18734294MTEyjMDcb1] [PMID: 33280598]
[21]
Gobbi, A.; Lee, M.L. DISE: Directed sphere exclusion. J. Chem. Inf. Comput. Sci., 2003, 43(1), 317-323.
[http://dx.doi.org/10.1021/ci025554v] [PMID: 12546567]
[22]
Hudson, B.D.; Hyde, R.M.; Rahr, E.; Wood, J.; Osman, J. Parameter based methods for compound selection from chemical databases. Quant. Struct.-Act. Relationsh., 1996, 15(4), 285-289.
[http://dx.doi.org/10.1002/qsar.19960150402]
[23]
Validation of (Q)SAR Models - OECD. Available from: https://www.oecd.org/chemicalsafety/risk-assessment/validationofqsarmodels.htm (accessed February 3, 2022).
[24]
de Haas, E.M.; Eikelboom, T.; Bouwman, T. Internal and external validation of the long-term QSARs for neutral organics to fish from ECOSAR™. SAR QSAR Environ. Res., 2011, 22(5-6), 545-559.
[http://dx.doi.org/10.1080/1062936X.2011.569949] [PMID: 21732893]
[25]
Alam, S.; Khan, F. Virtual screening, docking, ADMET and system pharmacology studies on Garcinia caged Xanthone derivatives for anticancer activity. Sci. Rep., 2018, 8(1), 5524.
[http://dx.doi.org/10.1038/s41598-018-23768-7] [PMID: 29615704]
[26]
Alam, S.; Khan, F. QSAR, docking, ADMET, and system pharmacology studies on tormentic acid derivatives for anticancer activity. J. Biomol. Struct. Dyn., 2018, 36(9), 2373-2390.
[http://dx.doi.org/10.1080/07391102.2017.1355846] [PMID: 28705120]
[27]
Szklarczyk, D.; Santos, A.; von Mering, C.; Jensen, L.J.; Bork, P.; Kuhn, M. STITCH 5: Augmenting protein–chemical interaction networks with tissue and affinity data. Nucleic Acids Res., 2016, 44(D1), D380-D384.
[http://dx.doi.org/10.1093/nar/gkv1277] [PMID: 26590256]
[28]
Bhukya, B.; Alam, S.; Chaturvedi, V.; Trivedi, P.; Kumar, S.; Khan, F. Brevifoliol and its analogs: A new class of antitubercular agents. Curr. Top. Med. Chem., 2021, 21(9), 767-776.
[http://dx.doi.org/10.2174/1568026620666200528155236] [PMID: 32484109]
[29]
Feroz Khan, F.; Alam, S. QSAR and docking studies on xanthone derivatives for anticancer activity targeting DNA topoisomerase IIα. Drug Des. Devel. Ther., 2014, 8, 183-195.
[http://dx.doi.org/10.2147/DDDT.S51577] [PMID: 24516330]
[30]
Iqbal, H.; Verma, A.K.; Yadav, P.; Alam, S.; Shafiq, M.; Mishra, D.; Khan, F.; Hanif, K.; Negi, A.S.; Chanda, D. Antihypertensive effect of a novel angiotensin II receptor blocker fluorophenyl benzimidazole: Contribution of cGMP, voltage-dependent calcium channels, and BKCa channels to vasorelaxant mechanisms. Front. Pharmacol., 2021, 12, 611109.
[http://dx.doi.org/10.3389/fphar.2021.611109] [PMID: 33859561]
[31]
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings 1PII of original article: S0169-409X(96)00423-1. The article was originally published in advanced drug delivery reviews 23 (1997) 3–25. 1. Adv. Drug Deliv. Rev., 2001, 46(1-3), 3-26.
[http://dx.doi.org/10.1016/S0169-409X(00)00129-0] [PMID: 11259830]
[32]
Ghose, A.K.; Viswanadhan, V.N.; Wendoloski, J.J. A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J. Comb. Chem., 1999, 1(1), 55-68.
[http://dx.doi.org/10.1021/cc9800071] [PMID: 10746014]
[33]
Veber, D.F.; Johnson, S.R.; Cheng, H.Y.; Smith, B.R.; Ward, K.W.; Kopple, K.D. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem., 2002, 45(12), 2615-2623.
[http://dx.doi.org/10.1021/jm020017n] [PMID: 12036371]
[34]
Egan, W.J.; Merz, K.M., Jr; Baldwin, J.J. Prediction of drug absorption using multivariate statistics. J. Med. Chem., 2000, 43(21), 3867-3877.
[http://dx.doi.org/10.1021/jm000292e] [PMID: 11052792]
[35]
Muegge, I.; Heald, S.L.; Brittelli, D. Simple selection criteria for drug-like chemical matter. J. Med. Chem., 2001, 44(12), 1841-1846.
[http://dx.doi.org/10.1021/jm015507e] [PMID: 11384230]
[36]
Martin, Y.C. A bioavailability score. J. Med. Chem., 2005, 48(9), 3164-3170.
[http://dx.doi.org/10.1021/jm0492002] [PMID: 15857122]
[37]
Baell, J.B.; Holloway, G.A. New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J. Med. Chem., 2010, 53(7), 2719-2740.
[http://dx.doi.org/10.1021/jm901137j] [PMID: 20131845]
[38]
Brenk, R.; Schipani, A.; James, D.; Krasowski, A.; Gilbert, I.H.; Frearson, J.; Wyatt, P.G. Lessons learnt from assembling screening libraries for drug discovery for neglected diseases. ChemMedChem, 2008, 3(3), 435-444.
[http://dx.doi.org/10.1002/cmdc.200700139] [PMID: 18064617]
[39]
Teague, S.J.; Davis, A.M.; Leeson, P.D.; Oprea, T. The design of leadlike combinatorial libraries. Angew. Chem. Int. Ed., 1999, 38(24), 3743-3748.
[http://dx.doi.org/10.1002/(SICI)1521-3773(19991216)38:24<3743::AID-ANIE3743>3.0.CO;2-U] [PMID: 10649345]
[40]
Boda, K.; Seidel, T.; Gasteiger, J. Structure and reaction based evaluation of synthetic accessibility. J. Comput. Aided Mol. Des., 2007, 21(6), 311-325.
[http://dx.doi.org/10.1007/s10822-006-9099-2] [PMID: 17294248]
[41]
Alam, S.; Khan, F. 3D-QSAR studies on maslinic acid analogs for anticancer activity against breast cancer cell line MCF-7. Sci. Rep., 2017, 7(1), 6019.
[http://dx.doi.org/10.1038/s41598-017-06131-0] [PMID: 28729623]
[42]
Doyle, A.; Griffiths, J.B. Mammalian cell culture: Essential techniques; Wiley, 1997.
[43]
Wang, M.; Zhang, Y.; Wang, T.; Zhang, J.; Zhou, Z.; Sun, Y.; Wang, S.; Shi, Y.; Luan, X.; Zhang, Y.; Wang, Y.; Wang, Y.; Zou, Z.; Kang, L.; Liu, H. The USP7 inhibitor P5091 induces cell death in ovarian cancers with different P53 status. Cell. Physiol. Biochem., 2017, 43(5), 1755-1766.
[http://dx.doi.org/10.1159/000484062] [PMID: 29049989]
[44]
Kulkarni, P.S.; Kondhare, D.D.; Varala, R.; Zubaidha, P.K. Calcium hydroxide: An efficient and mild base for one-pot synthesis of curcumin and it’s analogues. Acta Chim. Slov., 2013, 6(1), 150-156.
[http://dx.doi.org/10.2478/acs-2013-0023]

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