Sesquiterpene Lactones as Potential Cyclin B1/CDK1 Complex Inhibitors
Sesquiterpene Lactones as Potential Cyclin B1/CDK1
Keywords:Cell Cycle Arrest, Cyclin B1, CDK1, Sesquiterpene Lactones, Molecular Docking
Cancer is second most common cause of death globally. Uncontrolled regulation of cell cycle may cause various cancerous anomalies. Objective: To Identify of Sesquiterpene Lactones (SLs) as inhibitors of Cyclin B1 (CB1) and Cyclin Dependent Kinase 1 (CDK1) complex. Methods: Checkpoints proteins (CDK1/CB1) of G2/M phase have been assessed with three SLs (ilicol, eucalyptone and ascleposide E) through molecular docking study. AutoDock Vina (ADV), PyMol version-2.5.2 and BIOVIA Discovery Studio 2021 was used for the visualization of docking analysis. Results: Outcomes of the current investigations reveal that ascleposide E exhibit the highest binding affinity of -7.1 kcal/mol (with inhibition constant of 5.9 µM) with CDK1 and CB1. Both potential complexes have shown good hydrogen bond interactions. Drug likeness of selected drug candidates were validated by ADMET analysis and Lipinski’s rule of 5. Conclusions: Present study concluded that Ascleposide E have greater inhibition potential against CB1/CDK1 protein complex by making hydrogen and hydrophobic interactions. Moreover, this selected compound showed favorable drug likeness profiling. To validate the inhibitory activity of Ascleposide E to greater extent, further in vitro investigations are recommended to develop this compound into novel G2/M phase inhibitors.
Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA: A Cancer Journal for Clinicians. 2023 Jan; 73(1): 17-48. doi: 10.3322/caac.21763.
Khan M, Maryam A, Zhang H, Mehmood T, Ma T. Killing cancer with platycodin D through multiple mechanisms. Journal of Cellular and Molecular Medicine. 2016 Mar; 20(3): 389-402. doi: 10.1111/jcmm.12749.
Javed A, Yarmohammadi M, Korkmaz KS, Rubio-Tomás T. The Regulation of Cyclins and Cyclin-Dependent Kinases in the Development of Gastric Cancer. International Journal of Molecular Sciences. 2023 Feb; 24(3): 2848. doi: 10.3390/ijms24032848.
Gousias K, Theocharous T, Simon M. Mechanisms of cell cycle arrest and apoptosis in glioblastoma. Biomedicines. 2022 Feb; 10(3): 564. doi: 10.3390/biomedicines10030564.
Sunada S, Saito H, Zhang D, Xu Z, Miki Y. CDK1 inhibitor controls G2/M phase transition and reverses DNA damage sensitivity. Biochemical and Biophysical Research Communications. 2021 Apr; 550: 56-61. doi: 10.1016/j.bbrc.2021.02.117.
Khan M, Maryam A, Qazi JI, Ma T. Targeting apoptosis and multiple signaling pathways with icariside II in cancer cells. International Journal of Biological Sciences. 2015 Jul; 11(9): 1100. doi: 10.7150/ijbs.11595.
Aliarab A, Abroon S, Rasmi Y, Aziz SG. Application of sesquiterpene lactone: A new promising way for cancer therapy based on anticancer activity. Biomedicine & Pharmacotherapy. 2018 Oct; 106: 239-46. doi: 10.1016/j.biopha.2018.06.131.
Paço A, Brás T, Santos JO, Sampaio P, Gomes AC, Duarte MF. Anti-inflammatory and immunoregulatory action of sesquiterpene lactones. Molecules. 2022 Feb; 27(3): 1142. doi: 10.3390/molecules27031142.
Laurella LC, Mirakian NT, Garcia MN, Grasso DH, Sülsen VP, Papademetrio DL. Sesquiterpene lactones as promising candidates for cancer therapy: Focus on pancreatic cancer. Molecules. 2022 May; 27(11): 3492. doi: 10.3390/molecules27113492.
Asiamah I, Obiri SA, Tamekloe W, Armah FA, Borquaye LS. Applications of Molecular Docking in Natural Products-Based Drug Discovery. Scientific African. 2023 Feb: e01593. doi: 10.1016/j.sciaf.2023.e01593.
Fan J, Fu A, Zhang L. Progress in molecular docking. Quantitative Biology. 2019 Jun; 7: 83-9. doi: 10.1007/s40484-019-0172-y.
Morris GM and Lim-Wilby M. Molecular docking. Molecular modeling of proteins. 2008: 365-82. doi: 10.1007/978-1-59745-177-2_19.
Narkhede RR, Cheke RS, Ambhore JP, Shinde SD. The molecular docking study of potential drug candidates showing anti-COVID-19 activity by exploring of therapeutic targets of SARS-CoV-2. Eurasian Journal of Medicine and Oncology. 2020 Apr; 4(3): 185-95.
Curreli F, Kwon YD, Belov DS, Ramesh RR, Kurkin AV, Altieri A, et al. Synthesis, antiviral potency, in vitro ADMET, and X-ray structure of potent CD4 mimics as entry inhibitors that target the Phe43 cavity of HIV-1 gp120. Journal of Medicinal Chemistry. 2017 Apr; 60(7): 3124-53. doi: 10.1021/acs.jmedchem.7b00179.
Pires DE, Blundell TL, Ascher DB. pkCSM: predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. Journal of medicinal chemistry. 2015 May; 58(9): 4066-72. doi: 10.1021/acs.jmedchem.5b00104.
Karadeniz F, Oh JH, Kong CS. Sesquiterpene lactones: A review of biological activities. 생명과학회지. 2021 Apr; 31(4): 430-41.
Du X, Li Y, Xia YL, Ai SM, Liang J, Sang P, et al. Insights into protein–ligand interactions: mechanisms, models, and methods. International Journal of Molecular Sciences. 2016 Jan; 17(2): 144. doi: 10.3390/ijms17020144.
Sousa SF, Ribeiro AJ, Coimbra JT, Neves RP, Martins SA, Moorthy NS, et al. Protein-ligand docking in the new millennium–a retrospective of 10 years in the field. Current Medicinal Chemistry. 2013 Jun; 20(18): 2296-314. doi: 10.2174/0929867311320180002.
Makita Y, Saito S, Tsuchiya A, Ishibashi M, Arai MA. Identification of 1β, 2α-epoxytagitinin C as a Notch inhibitor, oxidative stress mechanism and its anti-leukemia activity. Journal of Natural Medicines. 2022 Jan; 76: 234-43. doi: 10.1007/s11418-021-01584-0.
Bailly C and Vergoten G. Japonicone A and related dimeric sesquiterpene lactones: Molecular targets and mechanisms of anticancer activity. Inflammation Research. 2022 Jan: 1-0. doi: 10.1007/s00011-021-01538-y.
Li Q, Wang Z, Xie Y, Hu H. Antitumor activity and mechanism of costunolide and dehydrocostus lactone: Two natural sesquiterpene lactones from the Asteraceae family. Biomedicine & Pharmacotherapy. 2020 May; 125: 109955. doi: 10.1016/j.biopha.2020.109955.
Sztiller-Sikorska M and Czyz M. Parthenolide as cooperating agent for anti-cancer treatment of various malignancies. Pharmaceuticals. 2020 Aug; 13(8): 194. doi: 10.3390/ph13080194.
Lipinski CA. Lead-and drug-like compounds: the rule-of-five revolution. Drug discovery today: Technologies. 2004 Dec; 1(4): 337-41. doi: 10.1016/j.ddtec.2004.11.007.
Mathialagan S, Piotrowski MA, Tess DA, Feng B, Litchfield J, Varma MV. Quantitative prediction of human renal clearance and drug-drug interactions of organic anion transporter substrates using in vitro transport data: a relative activity factor approach. Drug Metabolism and Disposition. 2017 Apr; 45(4): 409-17. doi: 10.1124/dmd.116.074294.
Radchenko EV, Dyabina AS, Palyulin VA, Zefirov NS. Prediction of human intestinal absorption of drug compounds. Russian Chemical Bulletin. 2016 Feb; 65: 576-80. doi: 10.1007/s11172-016-1340-0.
Flores‐Holguín N, Frau J, Glossman‐Mitnik D. Computational Pharmacokinetics Report, ADMET Study and Conceptual DFT‐Based Estimation of the Chemical Reactivity Properties of Marine Cyclopeptides. ChemistryOpen. 2021 Nov; 10(11): 1142-9. doi: 10.1002/open.202100178.
Lund M, Petersen TS, Dalhoff KP. Clinical implications of P-glycoprotein modulation in drug–drug interactions. Drugs. 2017 May; 77(8): 859-83. doi: 10.1007/s40265-017-0729-x.
Llorach-Pares L, Nonell-Canals A, Sanchez-Martinez M, Avila C. Computer-aided drug design applied to marine drug discovery: Meridianins as Alzheimer’s disease therapeutic agents. Marine Drugs. 2017 Nov; 15(12): 366. doi: 10.3390/md15120366.
Muhammad S, Hassan SH, Al-Sehemi AG, Shakir HA, Khan M, Irfan M, et al. Exploring the new potential antiviral constituents of Moringa oliefera for SARS-COV-2 pathogenesis: An in silico molecular docking and dynamic studies. Chemical Physics Letters. 2021 Mar; 767: 138379. doi: 10.1016/j.cplett.2021.138379.
Tracy TS, Chaudhry AS, Prasad B, Thummel KE, Schuetz EG, Zhong XB, et al. Interindividual variability in cytochrome P450–mediated drug metabolism. Drug Metabolism and Disposition. 2016 Mar; 44(3): 343-51. doi: 10.1124/dmd.115.067900.
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