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Medicinal Chemistry

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ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

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Research Article

Natural Products as a Major Source of Candidates for Potential Senolytic Compounds obtained by in silico Screening

Author(s): Oscar S. Barrera-Vázquez, Gil A. Magos-Guerrero*, Juan L. Escobar-Ramírez and Juan C. Gomez-Verjan

Volume 19, Issue 7, 2023

Published on: 07 December, 2022

Page: [653 - 668] Pages: 16

DOI: 10.2174/1573406419666221019153537

Price: $65

Abstract

Background: Preclinical studies suggest that senolytic compounds such as quercetin (a natural product) and dasatinib (a synthetic product) decrease senescent cells, reduce inflammation, and alleviate human frailty. This evidence has opened a new field of research for studying the effect of these compounds on age-related dysfunction and diseases.

Objective: The present study performed in silico and we identified new potential senolytic candidates from an extensive database that contains natural products (NPs) and semi-synthetic products (SMSs).

Methods: Computer programs Chemminer and rcdk packages, which compared the fingerprints of numerous molecules (40,383) with reference senolytics, and the creation of a pharmacological network built with signaling pathways and targets involved in senescence processes were used to identify compounds with a potential activity.

Results: Six drug-like candidates (3,4'-dihydroxypropiophenone, baicalein, α, β-dehydrocurvularin, lovastatin, luteolin, and phloretin) were identified.

Conclusion: To our knowledge, this is the first time that these six natural molecules have been proposed to have senolytic activity. To validate the methodology employed in the identification of new drug-like senolytics, experimental evidence is needed with models that evaluate senolytic activity.

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[1]
Kirkland, J.L.; Tchkonia, T. Senolytic drugs: From discovery to translation. J. Intern. Med., 2020, 288(5), 518-536.
[http://dx.doi.org/10.1111/joim.13141] [PMID: 32686219]
[2]
Van Deursen, J.M. The role of senescent cells in ageing. Nature, 2014, 509(7501), 439-446.
[http://dx.doi.org/10.1038/nature13193] [PMID: 24848057]
[3]
Childs, B.G.; Durik, M.; Baker, D.J.; Van Deursen, J.M. Cellular senescence in aging and age-related disease: From mechanisms to therapy. Nat. Med., 2015, 21(12), 1424-1435.
[http://dx.doi.org/10.1038/nm.4000] [PMID: 26646499]
[4]
Trendelenburg, A.U.; Scheuren, A.C.; Potter, P.; Müller, R.; Bellantuono, I. Geroprotectors: A role in the treatment of frailty. Mech. Ageing Dev., 2019, 180, 11-20.
[http://dx.doi.org/10.1016/j.mad.2019.03.002] [PMID: 30885572]
[5]
Justice, J.N.; Nambiar, A.M.; Tchkonia, T.; LeBrasseur, N.K.; Pascual, R.; Hashmi, S.K.; Prata, L.; Masternak, M.M.; Kritchevsky, S.B.; Musi, N.; Kirkland, J.L. Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. EBioMedicine, 2019, 40, 554-563.
[http://dx.doi.org/10.1016/j.ebiom.2018.12.052] [PMID: 30616998]
[6]
Hickson, L.J.; Langhi, P.L.G.P.; Bobart, S.A.; Evans, T.K.; Giorgadze, N.; Hashmi, S.K.; Herrmann, S.M.; Jensen, M.D.; Jia, Q.; Jordan, K.L.; Kellogg, T.A.; Khosla, S.; Koerber, D.M.; Lagnado, A.B.; Lawson, D.K.; LeBrasseur, N.K.; Lerman, L.O.; McDonald, K.M.; McKenzie, T.J.; Passos, J.F.; Pignolo, R.J.; Pirtskhalava, T.; Saadiq, I.M.; Schaefer, K.K.; Textor, S.C.; Victorelli, S.G.; Volkman, T.L.; Xue, A.; Wentworth, M.A.; Wissler, G.E.O.; Zhu, Y.; Tchkonia, T.; Kirkland, J.L. Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease. EBio. Med., 2019, 47, 446-456.
[http://dx.doi.org/10.1016/j.ebiom.2019.08.069] [PMID: 31542391]
[7]
Thoppil, H.; Riabowol, K. Senolytics: A translational bridge between cellular senescence and organismal aging. Front. Cell Dev. Biol., 2020, 7, 367-367.
[http://dx.doi.org/10.3389/fcell.2019.00367] [PMID: 32039197]
[8]
Barrera, V.O.S.; Gómez, V.J.C.; Magos, G.G.A. Chemoinformatic screening for the selection of potential senolytic compounds from natural products. Biomolecules, 2021, 11(3), 467.
[http://dx.doi.org/10.3390/biom11030467] [PMID: 33809876]
[9]
Salekeen, R.; Barua, J.; Shaha, P.R.; Islam, K.M.D.; Islam, M.E.; Billah, M.M.; Rahman, S.M.M. Marine phycocompound screening reveals a potential source of novel senotherapeutics. J. Biomol. Struct. Dyn., 2022, 40(13), 6071-6085.
[http://dx.doi.org/10.1080/07391102.2021.1877822] [PMID: 33533325]
[10]
Sorokina, M.; Steinbeck, C. Review on natural products databases: Where to find data in 2020. J. Cheminform., 2020, 12(1), 20.
[http://dx.doi.org/10.1186/s13321-020-00424-9] [PMID: 33431011]
[11]
Bickerton, G.R.; Paolini, G.V.; Besnard, J.; Muresan, S.; Hopkins, A.L. Quantifying the chemical beauty of drugs. Nat. Chem., 2012, 4(2), 90-98.
[http://dx.doi.org/10.1038/nchem.1243] [PMID: 22270643]
[12]
O’Hagan, S.; Kell, D.B. Structural similarities between some common fluorophores used in biology, marketed drugs, endogenous metabolites, and natural products. Mar. Drugs, 2020, 18(11), 582.
[http://dx.doi.org/10.3390/md18110582] [PMID: 33238416]
[13]
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]
[14]
Gu, J.; Gui, Y.; Chen, L.; Yuan, G.; Lu, H.Z.; Xu, X. Use of natural products as chemical library for drug discovery and network pharmacology. PLoS One, 2013, 8(4), e62839.
[http://dx.doi.org/10.1371/journal.pone.0062839] [PMID: 23638153]
[15]
Wenderski, T.A.; Stratton, C.F.; Bauer, R.A.; Kopp, F.; Tan, D.S. Principal component analysis as a tool for library design: A case study investigating natural products, brand-name drugs, natural product-like libraries, and drug-like libraries. Methods Mol. Biol., 2015, 1263, 225-242.
[http://dx.doi.org/10.1007/978-1-4939-2269-7_18] [PMID: 25618349]
[16]
Voicu, A.; Duteanu, N.; Voicu, M.; Vlad, D.; Dumitrascu, V. The rcdk and cluster R packages applied to drug candidate selection. J. Cheminform., 2020, 12(1), 3.
[http://dx.doi.org/10.1186/s13321-019-0405-0] [PMID: 33430987]
[17]
Kim, S.; Chen, J.; Cheng, T.; Gindulyte, A.; He, J.; He, S.; Li, Q.; Shoemaker, B.A.; Thiessen, P.A.; Yu, B.; Zaslavsky, L.; Zhang, J.; Bolton, E.E. PubChem 2019 update: Improved access to chemical data. Nucleic Acids Res., 2019, 47(D1), D1102-D1109.
[http://dx.doi.org/10.1093/nar/gky1033] [PMID: 30371825]
[18]
Malhat, M.G.; Mousa, H.M.; El-Sisi, A.B. Parallel ward clustering for chemical compounds using mapreduce. In: International Conference on Advanced Machine Learning Technologies and Applications; Springer; Germany, 2014; pp. 258-267.
[http://dx.doi.org/10.1007/978-3-319-13461-1_25]
[19]
Martens, M.; Ammar, A.; Riutta, A.; Waagmeester, A.; Slenter, D.N.; Hanspers, K.; Miller, A. R.; Digles, D.; Lopes, E.N.; Ehrhart, F.; Dupuis, L.J.; Winckers, L.A.; Coort, S.L.; Willighagen, E.L.; Evelo, C.T.; Pico, A.R.; Kutmon, M. WikiPathways: Connecting communities. Nucleic Acids Res., 2021, 49(D1), D613-D621.
[http://dx.doi.org/10.1093/nar/gkaa1024] [PMID: 33211851]
[20]
Shannon, P.; Markiel, A.; Ozier, O.; Baliga, N.S.; Wang, J.T.; Ramage, D.; Amin, N.; Schwikowski, B.; Ideker, T. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res., 2003, 13(11), 2498-2504.
[http://dx.doi.org/10.1101/gr.1239303] [PMID: 14597658]
[21]
Ononye, S.N.; VanHeyst, M.D.; Oblak, E.Z.; Zhou, W.; Ammar, M.; Anderson, A.C.; Wright, D.L. Tropolones as lead-like natural products: The development of potent and selective histone deacetylase inhibitors. ACS Med. Chem. Lett., 2013, 4(8), 757-761.
[http://dx.doi.org/10.1021/ml400158k] [PMID: 24900743]
[22]
Tsuchida, K.; Chaki, H.; Takakura, T.; Yokotani, J.; Aikawa, Y.; Shiozawa, S.; Gouda, H.; Hirono, S. Design, synthesis, and biological evaluation of new cyclic disulfide decapeptides that inhibit the binding of AP-1 to DNA. J. Med. Chem., 2004, 47(17), 4239-4246.
[http://dx.doi.org/10.1021/jm049890+] [PMID: 15293995]
[23]
PubChem Bioassay Record for AID 1436, Homologous Recombination_Rad51_DNA binding assay. 2021. Available from: https://pubchem.ncbi.nlm.nih.gov/bioassay/1436
[24]
Achenbach, H.; Waibel, R.; Addae, M.I. Lignans and other constituents from Carissa edulis. Phytochemistry, 1983, 22(3), 749-753.
[http://dx.doi.org/10.1016/S0031-9422(00)86976-9]
[25]
Sowndhararajan, K.; Deepa, P.; Kim, M.; Park, S.J.; Kim, S. Baicalein as a potent neuroprotective agent: A review. Biomed. Pharmacother., 2017, 95, 1021-1032.
[http://dx.doi.org/10.1016/j.biopha.2017.08.135] [PMID: 28922719]
[26]
Kumar, C.G.; Mongolla, P.; Sujitha, P.; Joseph, J.; Babu, K.S.; Suresh, G.; Ramakrishna, K.V.S.; Purushotham, U.; Sastry, G.N.; Kamal, A. Metabolite profiling and biological activities of bioactive compounds produced by Chrysosporium lobatum strain BK-3 isolated from Kaziranga National Park, Assam, India. Springerplus, 2013, 2(1), 122-122.
[http://dx.doi.org/10.1186/2193-1801-2-122] [PMID: 23565355]
[27]
Bhargavi, S.; Praveen, V.; Marium, S.; Sreepriya, M.; Savitha, J. Purification of lovastatin from Aspergillus terreus (KM017963) and evaluation of its anticancer and antioxidant properties. Asian Pac. J. Cancer Prev., 2016, 17(8), 3797-3803.
[PMID: 27644619]
[28]
Lin, Y.; Shi, R.; Wang, X.; Shen, H.M. Luteolin, a flavonoid with potential for cancer prevention and therapy. Curr. Cancer Drug Targets, 2008, 8(7), 634-646.
[http://dx.doi.org/10.2174/156800908786241050] [PMID: 18991571]
[29]
Mariadoss, A.V.A.; Vinyagam, R.; Rajamanickam, V.; Sankaran, V.; Venkatesan, S.; David, E. Pharmacological aspects and potential use of phloretin: A systemic review. Mini Rev. Med. Chem., 2019, 19(13), 1060-1067.
[http://dx.doi.org/10.2174/1389557519666190311154425] [PMID: 30864525]
[30]
Duan, H.; Wang, R.; Yan, X.; Liu, H.; Zhang, Y.; Mu, D.; Han, J.; Li, X. Phloretin induces apoptosis of human esophageal cancer via a mitochondria dependent pathway. Oncol. Lett., 2017, 14(6), 6763-6768.
[http://dx.doi.org/10.3892/ol.2017.7037] [PMID: 29151915]
[31]
Lahlou, M. The success of natural products in drug discovery. Pharmacol. Pharm., 2013, 4(3), 17-31.
[http://dx.doi.org/10.4236/pp.2013.43A003]
[32]
Salehi, B.; Machin, L.; Monzote, L.; Sharifi, R.J.; Ezzat, S.M.; Salem, M.A.; Merghany, R.M.; El Mahdy, N.M.; Kılıç, C.S.; Sytar, O.; Sharifi, R.M.; Sharopov, F.; Martins, N.; Martorell, M.; Cho, W.C. Therapeutic potential of quercetin: New insights and perspectives for human health. ACS Omega, 2020, 5(20), 11849-11872.
[http://dx.doi.org/10.1021/acsomega.0c01818] [PMID: 32478277]
[33]
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]
[34]
Wanat, K. Biological barriers, and the influence of protein binding on the passage of drugs across them. Mol. Biol. Rep., 2020, 47(4), 3221-3231.
[http://dx.doi.org/10.1007/s11033-020-05361-2] [PMID: 32140957]
[35]
Lagoumtzi, S.M.; Chondrogianni, N. Senolytics and senomorphics: Natural and synthetic therapeutics in the treatment of aging and chronic diseases. Free Radic. Biol. Med., 2021, 171, 169-190.
[http://dx.doi.org/10.1016/j.freeradbiomed.2021.05.003] [PMID: 33989756]
[36]
Docherty, M.H.; Baird, D.P.; Hughes, J.; Ferenbach, D.A. Cellular senescence and senotherapies in the kidney: Current evidence and future directions. Front. Pharmacol., 2020, 11(755), 755.
[http://dx.doi.org/10.3389/fphar.2020.00755] [PMID: 32528288]
[37]
Li, J.; Zhou, Y.; Du, G.; Qin, X.; Gao, L. Integration of transcriptomics and network analysis deciphers the mechanisms of baicalein in improving learning and memory impairment in Senescence-Accelerated Mouse Prone 8 (SAMP8). Eur. J. Pharmacol., 2019, 865, 172789.
[http://dx.doi.org/10.1016/j.ejphar.2019.172789] [PMID: 31715136]
[38]
Gao, L.; Zheng, W.; Wu, X.; Du, G.; Qin, X.; Baicalein, D.H. Baicalein delays H 2 O 2 -induced astrocytic senescence through inhibition of Senescence-Associated Secretory Phenotype (SASP), suppression of JAK2/STAT1/NF-κB pathway, and regulation of leucine metabolism. ACS Chem. Neurosci., 2021, 12(13), 2320-2335.
[http://dx.doi.org/10.1021/acschemneuro.1c00024] [PMID: 34152720]
[39]
Gao, L.; Duan, D.; Zhang, J.; Zhou, Y.; Qin, X.; Du, G. A bioinformatic approach for the discovery of antiaging effects of baicalein from Scutellaria baicalensis Georgi. Rejuvenation Res., 2016, 19(5), 414-422.
[http://dx.doi.org/10.1089/rej.2015.1760] [PMID: 26778291]
[40]
Duan, D.; Wang, K.; Zhou, Y.; Qin, X.; Gao, L.; Du, G. Baicalein exerts beneficial effects in D -galactose-induced aging rats through attenuation of inflammation and metabolic dysfunction. Rejuvenation Res., 2017, 20(6), 506-516.
[http://dx.doi.org/10.1089/rej.2017.1919] [PMID: 28548620]
[41]
Wu, C.C.; Chen, Y.R.; Lu, D.H.; Hsu, L.H.; Yang, K.C.; Sumi, S. Evaluation of the post-treatment anti-inflammatory capacity of osteoarthritic chondrocytes: An in vitro study using baicalein. Regen. Ther., 2020, 14, 177-183.
[http://dx.doi.org/10.1016/j.reth.2020.02.002] [PMID: 32128354]
[42]
Lee, E.; Park, H.R.; Ji, S.T.; Lee, Y.; Lee, J. Baicalein attenuates astroglial activation in the 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine-induced Parkinson’s disease model by downregulating the activations of nuclear factor-κB, ERK, and JNK. J. Neurosci. Res., 2014, 92(1), 130-139.
[http://dx.doi.org/10.1002/jnr.23307] [PMID: 24166733]
[43]
Duan, D.D.; Gao, L.; Wang, K.X.; Qin, X.M.; Zhou, Y.Z.; Du, G.H. [Baicalein prolongs the lifespan of Drosophila melanogaster through antioxidation activity]. Yao Xue Xue Bao, 2016, 51(9), 1401-1406.
[PMID: 29924517]
[44]
Havermann, S.; Humpf, H.U.; Wätjen, W. Baicalein modulates stress-resistance and life span in C. elegans via SKN-1 but not DAF-16. Fitoterapia, 2016, 113, 123-127.
[http://dx.doi.org/10.1016/j.fitote.2016.06.018] [PMID: 27370100]
[45]
Kim, K.C.; Kang, S.S.; Lee, J.S.; Park, D.H.; Hyun, J.W. Baicalein attenuates oxidative stress-induced expression of matrix metalloproteinase-1 by regulating the ERK/JNK/AP-1 pathway in human keratinocytes. Biomol. Ther., 2012, 20(1), 57-61.
[http://dx.doi.org/10.4062/biomolther.2012.20.1.057] [PMID: 24116275]
[46]
Jeong, K.; Shin, Y.C.; Park, S.; Park, J.S.; Kim, N.; Um, J.Y.; Go, H.; Sun, S.; Lee, S.; Park, W.; Choi, Y.; Song, Y.; Kim, G.; Jeon, C.; Park, J.; Lee, K.; Bang, O.; Ko, S.G. Ethanol extract of Scutellaria baicalensis Georgi prevents oxidative damage and neuroinflammation and memorial impairments in artificial senescense mice. J. Biomed. Sci., 2011, 18(1), 14.
[http://dx.doi.org/10.1186/1423-0127-18-14] [PMID: 21299906]
[47]
Ayad, M.T.; Taylor, B.D.; Menon, R. Regulation of p38 mitogen-activated kinase-mediated fetal membrane senescence by statins. Am. J. Reprod. Immunol., 2018, 80(4), e12999.
[48]
Yudoh, K.; Karasawa, R. Statin prevents chondrocyte aging and degeneration of articular cartilage in Osteoarthritis (OA). Aging, 2010, 2(12), 990-998.
[http://dx.doi.org/10.18632/aging.100213] [PMID: 21098883]
[49]
Andreas, J.; Bo, S.; Gerhard, F.; Sebastian, H. Statins induce a DAF-16/foxo-dependent longevity phenotype via JNK-1 through mevalonate depletion in C. elegans. Aging Dis., 2020, 11(1), 60-72.
[http://dx.doi.org/10.14336/AD.2019.0416] [PMID: 32010481]
[50]
Liu, J.F.; Ma, Y.; Wang, Y.; Du, Z.Y.; Shen, J.K.; Peng, H.L. Reduction of lipid accumulation in HepG2 cells by luteolin is associated with activation of AMPK and Mitigation of oxidative stress. Phytother. Res., 2011, 25(4), 588-596.
[http://dx.doi.org/10.1002/ptr.3305] [PMID: 20925133]
[51]
Gendrisch, F.; Esser, P.R.; Schempp, C.M.; Wölfle, U. Luteolin as a modulator of skin aging and inflammation. Biofactors, 2021, 47(2), 170-180.
[http://dx.doi.org/10.1002/biof.1699] [PMID: 33368702]
[52]
Zhu, R.Z.; Li, B.S.; Gao, S.S.; Seo, J.H.; Choi, B.M. Luteolin inhibits H 2 O 2 -induced cellular senescence via modulation of SIRT1 and p53. Korean J. Physiol. Pharmacol., 2021, 25(4), 297-305.
[http://dx.doi.org/10.4196/kjpp.2021.25.4.297] [PMID: 34187948]
[53]
Burton, M.D.; Rytych, J.L.; Amin, R.; Johnson, R.W. Dietary luteolin reduces proinflammatory microglia in the brain of senescent mice. Rejuvenation Res., 2016, 19(4), 286-292.
[http://dx.doi.org/10.1089/rej.2015.1708] [PMID: 26918466]
[54]
Nabavi, S.F.; Braidy, N.; Gortzi, O.; Sobarzo, S.E.; Daglia, M.; Skalicka, W.K.; Nabavi, S. M. Luteolin as an anti-inflammatory and neuro-protective agent: A brief review. Brain Res. Bull., 2015, 119(Pt A), 1-11.
[http://dx.doi.org/10.1016/j.brainresbull.2015.09.002]
[55]
Anunciato, C.T.P.; Frank, L.A.; Pohlmann, A.R.; Guterres, S.S. Dermatological applications of the flavonoid phloretin. Eur. J. Pharmacol., 2020, 889, 173593.
[http://dx.doi.org/10.1016/j.ejphar.2020.173593] [PMID: 32971088]
[56]
Fuhrmann, S.H.; Ling, Y.Y.; Zhao, J.; McGowan, S.J.; Zhu, Y.; Brooks, R.W.; Grassi, D.; Gregg, S.Q.; Stripay, J.L.; Dorronsoro, A.; Corbo, L.; Tang, P.; Bukata, C.; Ring, N.; Giacca, M.; Li, X.; Tchkonia, T.; Kirkland, J.L.; Niedernhofer, L.J.; Robbins, P.D. Identification of HSP90 inhibitors as a novel class of senolytics. Nat. Commun., 2017, 8(1), 422-422.
[http://dx.doi.org/10.1038/s41467-017-00314-z] [PMID: 28871086]
[57]
Moskalev, A.; Chernyagina, E.; Kudryavtseva, A.; Shaposhnikov, M. Geroprotectors: A unified concept and screening approaches. Aging Dis., 2017, 8(3), 354-363.
[http://dx.doi.org/10.14336/AD.2016.1022] [PMID: 28580190]

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