In silico study of the pharmacological, toxicological activities of the secondary compounds of Zingiber officinale Roscoe and analysis of their possible interactions with targets of the inflammatory process
DOI:
https://doi.org/10.47456/hb.v5i2.44631Keywords:
Zingiber officinale, inflammation, mutagenicity, carcinogenicityAbstract
Data obtained in 195 countries in 2017 revealed that asthma reached 43.12 million new cases/year and that anti-inflammatory medications, antihistamines and sometimes medicinal plants, such as ginger (Zingiber officinale Roscoe), are used to treat this pathology. The objective of this study was to analyze the pharmacological and toxicological profile, in silico, of the main secondary compounds of Zingiber officinale Roscoe and the molecular interactions with pharmacological targets of importance in the inflammatory process. To this end, we searched for chemical structures and activities of the compounds with scientific evidence, pharmacokinetic and toxicological evaluations, in silico, on online servers, as well as molecular docking. Twelve molecules were used, with emphasis on gingerols, paradol and shogaols, as they are the main compounds of the rhizome in quantity and pharmacological action, which presented a relevant percentage of affinity for 5LOX, according to the SwissTarget Prediction platform. The preADMET platform also showed favorable ability to cross the blood-brain barrier and intestinal absorption, as well as high binding to plasma proteins. In addition, the main secondary compounds did not inhibit CYP3A4, did not show mutagenic potential in the Ames Test, presented moderate and low LD50 and low arrhythmogenic index, in addition to a moderate probability of carcinogenicity, mutagenicity, nephrotoxicity and toxicity in the respiratory system by ProTox III. The secondary compounds 6-shogaol and 6-paradol showed a higher probability of binding to the 5LOX target and demonstrated, statistically, similar docking to zileuton, favorable physicochemical and pharmacokinetic properties for oral use, in addition to the less toxic profile when compared to the other compounds, although they have immunotoxic potential and carcinogenic potential in mice.
Downloads
References
ALBUQUERQUE UPD, HANAZAKI N. As pesquisas etnodirigidas na descoberta de novos fármacos de interesse médico e farmacêutico: fragilidades e pespectivas. Rev Bras Farmacog 16: 678-689, 2006. DOI: https://doi.org/10.1590/S0102-695X2006000500015
ALEXANDRE ECB. Formulação de tintas para células solares orgânicas de alta eficiência através de parâmetros de solubilidade de Hansen. Trabalho de Conclusão de Curso (Graduação em Engenharia de Materiais), Centro de Tecnologia, Universidade Federal do Rio Grande do Norte, Natal, 2020, 62f.
ALI BH, BLUNDE G, TANIRA MO, NEMMAR A. Some phytochemical, pharmacological and toxicological properties of ginger (Zingiber officinale Roscoe): a review of recent research. Food Chem Toxicol 46(2): 409-420, 2008. DOI: https://doi.org/10.1016/j.fct.2007.09.085
AMARSAIKHAN N, ELSAWA SF. GLI2 (GLI family zinc finger 2). Atlas Genet. Cytogenet Oncol Haematol 2013. Disponível em https://atlasgeneticsoncology.org/gene/40718/gli2-(gli-family-zinc-finger-2). DOI: https://doi.org/10.4267/2042/51137
ARMBRUSTER D, MUELLER A, STROBEL A, LESCH KP, BROCKE B, KIRSCHBAUM C. Predicting cortisol stress responses in older individuals: influence of serotonin receptor 1A gene (HTR1A) and stressful life events. Horm Behav 60(1): 105-111, 2011. DOI: https://doi.org/10.1016/j.yhbeh.2011.03.010
BANERJEE P, KEMMLER E, DUNKEL M, PREISSNER R. ProTox 3.0: a webserver for the prediction of toxicity of chemicals. Nucleic Acids Res 52(W1):W513-W520, 2024. DOI: https://doi.org/10.1093/nar/gkae303
BARZEGAR S, PIROUZPANAH S. Zinc finger proteins and ATP‐binding cassette transporter‐dependent multidrug resistance. Eur J Clin Invest 54(2): e14120, 2023. DOI: https://doi.org/10.1111/eci.14120
BELLETI E, BEVILAQUA VR, BRITO AM, MODESTO DA, LANFREDI AJ, VIVIANI VR, NANTES-CARDOSO IL. Synthesis of bioluminescent gold nanoparticle–luciferase hybrid systems for technological applications. Photochem. Photobiol Sci 20: 1439-1453, 2021. DOI: https://doi.org/10.1007/s43630-021-00111-0
BRAZ CL, FIGUEIREDO TP, BARROSO SCC, REIS AMM. Medicamentos com atividade sobre o citocromo P450 utilizados por idosos em domicílio. Rev Méd Minas Gerais 28: 1-9, 2018. DOI: https://doi.org/10.5935/2238-3182.20180069
BRINGEZU F, SIMON S. Salmonella typhimurium TA100 and TA1535 and E. coli WP2 uvrA are highly sensitive to detect the mutagenicity of short Alkyl-N-Nitrosamines in the Bacterial Reverse Mutation Test. Toxicol Rep 9: 250-255, 2022. DOI: https://doi.org/10.1016/j.toxrep.2022.02.005
CAIXETA RA. Revisão narrativa sobre determinação da permeabilidade de fármacos por ensaios in vitro utilizando as células Caco-2. Monografia (Graduação em Farmácia), Escola de Farmácia, Universidade Federal de Ouro Preto, Ouro Preto, 2020, 45f.
CARVALHO, AF. Perfil epidemiológico dos casos de intoxicação por medicamentos registrados Centro de Informação e Assistência Toxicológica do Distrito Federal entre 2011 e 2016. Trabalho de Conclusão de Curso (Bacharelado em Farmácia), Universidade de Brasília, Brasília, 2017, 64f.
CHENGTAO PU, LINGQIAN GU, XINGYE C, YANMIN Z. Prediction of human intestinal absorption properties based on artificial intelligence. J China Pharm Univ 6: 355-362, 2023.
CHU-CHIN C, CHI-TAND H. Gas chromatographic analysis of thermal degradation products of gingerol compounds in steam-distilled oil from ginger (Zingiber officinale Roscoe). J. Chromatogr A 387: 499-504, 1987. DOI: https://doi.org/10.1016/S0021-9673(01)94559-5
DENISOV IG, GRINKOVA YV, NANDIGRAMI P, SHEKHAR M, TAJKHORSHID E, SLIGAR SG. Allosteric interactions in human cytochrome P450 CYP3A4: the role of phenylalanine 213. Biochemistry 58(10): 1411-1422, 2019. DOI: https://doi.org/10.1021/acs.biochem.8b01268
DOLABELA MF, SILVA ARPD, OHSASHI LH, BASTOS MLC, SILVA MCMD, VALE VV. Estudo in silico das atividades de triterpenos e iridoides isolados de Himatanthus articulatus (Vahl) Woodson. Rev Fitos (Rio J) 12(3): 227-242, 2018. DOI: https://doi.org/10.17648/2446-4775.2018.602
ETIENNE R, VIEGAS FPD, VIEGAS CJR. Aspectos fisiopatológicos da inflamação e o planejamento de fármacos: uma visão geral atualizada. Rev Virtual Quím 13(1): 167-191, 2021. DOI: https://doi.org/10.21577/1984-6835.20200138
GOES LMS. Análise do papel das ciclo-oxigenases e prostaglandina e sintase-1 microssomal na expressão de proteínas de matriz extracelular, integrinas e migração celular em gliobastoma. Dissertação (Mestrado em Biologia Celular e Tecidual), Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, 2020, 147f.
ISIKA DK, OZKOMEÇ FN, ÇESME M, SADIK OA. Synthesis, biological and computational studies of flavonoid acetamide derivatives. RSC Adv 12(16): 10037-10050, 2022. DOI: https://doi.org/10.1039/D2RA01375D
JING Y, EASTER A, PETERS D, KIM N, ENYEDY IJ. In silico prediction of hERG inhibition. Future Med Chem 7(5): 571-586, 2015. DOI: https://doi.org/10.4155/fmc.15.18
LEE CS, LEONG KW. Advances in microphysiological blood-brain barrier (BBB) models towards drug delivery. Curr Opin Biotechnol 66: 78-87, 2020. DOI: https://doi.org/10.1016/j.copbio.2020.06.009
LIMA AMA. Estudo in sílico de derivados semissintéticos da estemodina e obtenção de um composto mais ativo no controle de linhagem de células de carcinoma de cólon humano (HCT-116). Dissertação de Mestrado (Química Orgânica e Química Computacional), Universidade Federal do Ceará, Fortaleza, 2024, 74f.
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 DelivcRev 46(1-3): 3-26, 2001. DOI: https://doi.org/10.1016/S0169-409X(96)00423-1
LIU Q, SUN H, LIU Y, LI X, XU B, LI L, JIN W. HTR1A Inhibits the Progression of Triple‐Negative Breast Cancer via TGF‐β Canonical and Noncanonical Pathways. Adv Sci (Weinh) 9(12): e2105672, 2022. DOI: https://doi.org/10.1002/advs.202105672
MAHBOUBI, M. Zingiber officinale Rosc. essential oil, a review on its composition and bioactivity. Clin Phytosci 5(1): 1-12, 2019. DOI: https://doi.org/10.1186/s40816-018-0097-4
MILLANAO AR, MORA AY, VILLAGRA NA, BUCAREY SA, HIDALGO AA. Biological effects of quinolones: A family of broad-spectrum antimicrobial agents. Molecules 26(23): 7153, 2021. DOI: https://doi.org/10.3390/molecules26237153
MIRANDA CCS, SALAZAR VAC, COELHO AG. Predição in silico da atividade antiviral e avaliação de características farmacocinéticas e toxicológicas de compostos presentes no óleo essencial de Petiveria alliacea L. Rev Casos Consult 13(1): e30705-e30705, 2022.
MONTANHA FP, AZEVEDO MGP. Administração medicamentosa: vantagens e desvantagens das diferentes vias. Rev Cient Eletrônica Med Vet 10(20): 1-6, 2013.
MOTTA LF, PINTO CHS, ARAUJO LF. Análise Farmacocinética e Toxicológica in silico para Derivados do Ácido Cinâmico. In: OPEN SCIENCE RESEARCH X. Capítulo 56, Editora Científica Digital, 2023, p.749-765. DOI: https://doi.org/10.37885/230211899
MOURÃO PS. Identificação de compostos bioativos nos extratos etanólico das raízes e folhas da Cecropia pachystachya Tréc. e estudos in silico preADMET e docagem molecular com as enzimas 5-LOX e α-1-antitripsina. Dissertação (Programa de Pós-Graduação em Química), Universidade Estadual do Piauí, Teresina, 2022, 84f.
OLIVEIRA BG, ARAÚJO RCMU. SAPT: LIGAÇÃO DE HIDROGÊNIO OU INTERAÇÃO DE van der WAALS? Quim Nova 35(10): 2002-2012, 2012. DOI: https://doi.org/10.1590/S0100-40422012001000021
OLIVEIRA TS. Otimização do processo de extração do [6]-shogaol dos rizomas de zingiber officinale roscoe. Trabalho de Conclusão de Curso (Graduação em Farmácia), Universidade Federal de Sergipe, Lagarto, 2019, 43f.
PINHEIRO NR. Toxicidade de agregados do peptídeo beta-amiloide sobre a linhagem de neuroblastoma humano SH-SY5Y. Tese (Doutorado em Bioquímica), Faculdade de Medicina de Ribeirão Preto, Universidade São Paulo, Ribeirão Preto, https://doi.org/10.11606/T.17.2023.tde-08052023-103245, 2023. DOI: https://doi.org/10.11606/T.17.2023.tde-08052023-103245
PINTO PS, CARMINATTI M, LACET T, RODRIGUES DF, NOGUEIRA LO, BASTOS MG, FERNANDES M. Insuficiência renal aguda nefrotóxica: prevalência, evolução clínica e desfecho. J Bras Nefrol 31(3): 183-189, 2009. DOI: https://doi.org/10.1590/S0101-28002009000300003
PINZI L, RASTELLI G. Molecular docking: shifting paradigms in drug discovery. Int J Mol Sci 20(18): 4331, 2019. DOI: https://doi.org/10.3390/ijms20184331
PISZCZEK L, PISZCZEK A, KUCZMANSK J, AUDERO E, GROSS CT. Modulation of anxiety by cortical serotonin 1A receptors. Front Behav Neurosci 9: 48, doi: 10.3389/fnbeh.2015.00048, 2015. DOI: https://doi.org/10.3389/fnbeh.2015.00048
PIZZATTI L, KAWASSAKI ACB, FADEL B, NOGUEIRA FC, EVARISTO JA, WOLDMAR N, PANIS C. Toxicoproteomics disclose pesticides as downregulators of TNF-α, IL-1β and estrogen receptor pathways in breast cancer women chronically exposed. Front Oncol 10: 1698, doi: 10.3389/fonc.2020.01698, 2020. DOI: https://doi.org/10.3389/fonc.2020.01698
RAMOS BG, MARTINS TBD, DE CASTRO MEPC. Prevalência da asma nas regiões do Brasil: uma revisão sistemática Prevalence of asthma in Brazil’s five geographic regions: a systematic. Braz J Health Rev 4(3): 11341-11359, 2021. DOI: https://doi.org/10.34119/bjhrv4n3-133
REIS MS. Propriedades que influenciam a absorção de fármacos no trato gastrointestinal. Trabalho de Conclusão de Curso (Graduação em Farmácia), UniAGES, Paripiranga, 2022, 36f.
SALEA R, VERIANSYAH B, TJANDRAWINATA RR. Optimization and scale-up process for supercritical fluids extraction of ginger oil from Zingiber officinale var. Amarum. J Supercrit Fluids 120(2): 285-294, 2017. DOI: https://doi.org/10.1016/j.supflu.2016.05.035
SANTOS B, MEDEIROS JP, ALENCAR JAS, ALMEIDA JF, HOLANDA JKN, FARIAS JHA, SILVA NETO JV, MEDEIROS MAC, MORAIS LVS, COSTA ARN, MARTINS, RR, ANJOS RM, BRITO JÚNIOR L, ALMEIDA MGVM, OLIVEIRA FILHO AA. Educação fitoterápica e ambiental como meio de propagação do seu uso racional através da extensão universitária para a comunidade: relato de experiência. Res Soc Dev 9(10): e471910761, 2020. DOI: https://doi.org/10.33448/rsd-v9i10.7617
SARAVANAKUMAR A, SADIGHI A, RYU R, AKHLAGHI F. Physicochemical properties, biotransformation, and transport pathways of established and newly approved medications: a systematic review of the top 200 most prescribed drugs vs. the FDA-approved drugs between 2005 and 2016. Clin Pharmacokinet 58(10): 1281-1294, 2019. DOI: https://doi.org/10.1007/s40262-019-00750-8
SEYFINEJAD B, OZKAN SA, JOUYBAN A. Recent advances in the determination of unbound concentration and plasma protein binding of drugs: Analytical methods. Talanta 225: 122052, doi: 10.1016/j.talanta.2020.122052, 2021. DOI: https://doi.org/10.1016/j.talanta.2020.122052
SHARMA JN, MOHAMMED LA. The role of leukotrienes in the pathophysiology of inflammatory disorders: is there a case for revisiting leukotrienes as therapeutic targets? Inflammopharmacology 14(1-2): 10-16, 2006. DOI: https://doi.org/10.1007/s10787-006-1496-6
SILVA FRO. Planejamento de inibidores da enzima tripanotiona redutase utilizando ferramentas in silico. Dissertação (Mestrado), Centro de Ciências da Saúde, Universidade Federal de Santa Catarina, Programa de Pós-Graduação em Farmácia, Florianópolis, Santa Catarina, 2022.
SILVA HHM, ALVES MHP, GONÇALVES RJS, PEREIRA NA, AFFONSO CRG. Proposta de modificação molecular: análise de parâmetros físico-químicos, farmacocinéticos
e toxicológicos “in sílico” de fármacos barbitúricos. Res Soc Dev 11(13): e5291111335680-e5291111335680, 2022. DOI: https://doi.org/10.33448/rsd-v11i13.35680
SMITH CJ, ZHANG Y, KOBOLDT CM, MUHAMMAD J, ZWEIFEL BS, SHAFFER A, ISAKSON PC. Pharmacological analysis of cyclooxygenase-1 in inflammation. Proc Natl Acad Sci USA 95(22): 13313-13318, 1998. DOI: https://doi.org/10.1073/pnas.95.22.13313
SMITH WL, SONG I. The enzymology of prostaglandin endoperoxide H synthases-1 and-2. Prostaglandins Other Lipid Mediat 68-69: 115-128, 2002. DOI: https://doi.org/10.1016/S0090-6980(02)00025-4
SOLÉ D, NUNES ICC. A dimensão do problema da asma e da rinite alérgica no Brasil: prevalência, hospitalizações e mortalidade. GMBahia 78(2), 2009.
SOUSA JP, SARTURI L, ABREU AR, ARAÚJO de SOUSA T, MATIAS GOMES GERON VL. Breve relato sobre os efeitos terapêuticos do gengibre (Zingiber officinale Roscoe). Rev FAEMA, Ariquemes 10(1): 45-54, 2019. DOI: https://doi.org/10.31072/rcf.v10iedesp.785
SOUSA YRF, COSTA JÚNIOR JS, SILVA DC. Estudos in silico ADME para uma série de inibidores da enzima conversora da angiotensina (ECA). In: Anais do XXI Simpósio Brasileiro de Computação Aplicada à Saúde. SBC, 2021. p.416-421. DOI: https://doi.org/10.5753/sbcas.2021.16085
STANZIONE F, GIANGRECO I, COLE JC. Use of molecular docking computational tools in drug discovery. Prog Med Chem 60: 273-343, 2021. DOI: https://doi.org/10.1016/bs.pmch.2021.01.004
VASSELEK AJB. Estudo da toxicidade de compostos da classe triazenos. Trabalho de Conclusão de Curso (Licenciatura em Química), Universidade Tecnológica Federal do Paraná, Campo Mourão, Paraná, 2020.
YUEQIN Z. Identificación y actividad farmacológica de principios de especies antiinflamatorias. Tese (Doutorado em Farmacologia), Departamento de Farmacología, Universitat de València, España, 2006, 196f.
ZHOU, SF. Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4. Curr Drug Metab 9(4): 310-322, 2008. DOI: https://doi.org/10.2174/138920008784220664
