In silico Pharmacokinetic, Molecular Docking and Molecular Dynamics Simulation Studies of Phytochemicals isolated from Cascabela thevetia as Potential Anticancer Agents

Authors

  • Amit A Panday Department of Chemistry, M. L. K. (PG) College, Balrampur-271201, Uttar Pradesh, India
  • Ajay K Maurya Department of Chemistry, M. L. K. (PG) College, Balrampur-271201, Uttar Pradesh, India
  • Amit R Pandey APSH Department, Rajkiya Engineering College Ambedkar Nagar-2214122, Uttar Pradesh, India
  • Shivani Soni Department of Chemistry, M. L. K. (PG) College, Balrampur-271201, Uttar Pradesh, India
  • Shashank S Mishra School of Pharmaceuticals and Population Health Informatics, Faculty of Pharmacy, DIT University, Dehradun-248009, Uttarakhand, India
  • Rishi R Pandey Department of Chemistry, M. L. K. (PG) College, Balrampur-271201, Uttar Pradesh, India

Abstract

Cascabela thevetia generally recognized as yellow oleander, Lippold or lucky nut (in English) and Peeli Kaner (in Hindi), is Indigenous to Central America and Mexico and widely distributed in the Indian subcontinent as well, is a medicinally important herb that has long been employed to treat disorders like ulcers, scabies, haemorrhoids, and tumour dissolution. Seven Cardenolides (Compounds 1-7) isolated from fruits of Cascabela thevetia are selected as ligands for in silico pharmacokinetic (ADME properties) and drug-likeness studies via the Swiss ADME online server. Further, molecular docking studies were accomplished for the selected ligands via the Auto Dock Vina module of PyRx to explore the receptor-ligand interaction with β-tubulin (a potential target for anticancer drugs, PDB ID: 1SA0), to find out potential therapeutic ligands for cancer chemotherapy. From the studies performed it was found that most of the ligands (compounds) have the capability of good binding affinity with the receptor, β-tubulin, good drug-likeness and ADME properties among which compounds 3, 6 and 7 are the best drug candidates because they followed the Lipinski rule of 5 with 0 violation and also have good binding affinities (-8.3, -8.0 and -7.9 kcal/mol respectively) against the target protein. Hence, compounds 3, 6 and 7 can be developed as novel therapeutic agents in cancer chemotherapy. Further, a Molecular Dynamics (MD) simulation study of best-docked ligand 3 was performed to establish its stability and validate molecular docking results. Based on simulation results, it may be stated that ligand 3 was firmly attached to the receptor protein during MD simulation since none of the conformations of the receptor-ligand complex were unstable, and no folding or unfolding of the complex took place. Therefore, compound 3 can be considered a good inhibitor of β-tubulin after validation of various parameters of drug discovery.

Keywords:

Cancer, Cascabela thevetia, β-tubulin, molecular docking, Swiss ADME, Molecular Docking, MD simulation

DOI

https://doi.org/10.25004/IJPSDR.2024.160502

References

Cao W, Qin K, Li F, Chen W. Socioeconomic inequalities in cancer incidence and mortality: An analysis of GLOBOCAN 2022. Chin Med J (Engl). 2024 Jun 20;137(12):1407–13. doi: 10.1097/CM9.0000000000003140.

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov 12;68(6):394–424. doi: 10.3322/caac.21492.

Cella DF, Tulsky DS. Quality of Life in Cancer: Definition, Purpose, and Method of Measurement. Cancer Invest. 1993 Jan 11;11(3):327–36. doi: 10.3109/07357909309024860.

Sharma A, Arambula JF, Koo S, Kumar R, Singh H, Sessler JL, et al. Hypoxia-targeted drug delivery. Chem Soc Rev. 2019;48(3):771–813. doi: 10.1039/C8CS00304A.

Kim SK, Thomas NV, Li X. Anticancer compounds from marine macroalgae and their application as medicinal foods. Adv Food Nutr Res. 2011;64:213-24. doi: 10.1016/B978-0-12-387669-0.00016-8. PMID: 22054949.

Wen S, Chen Y, Lu Y, Wang Y, Ding L, Jiang M. Cardenolides from the Apocynaceae family and their anticancer activity. Fitoterapia. 2016 Jul;112:74–84. doi: 10.1016/j.fitote.2016.04.023.

Oji O, Okafor QE. Toxicological studies on stem bark, leaf and seed kernel of yellow oleander (Thevetia peruviana). Phyther Res. 2000 Mar;14(2):133–5. doi: 10.1002/(SICI)1099-1573(200003)14:2<133::AID-PTR598>3.0.CO;2-K.

Langford SD, Boor PJ. Oleander toxicity: an examination of human and animal toxic exposures. Toxicology. 1996 May;109(1):1–13. doi: 10.1016/0300-483X(95)03296-R.

Tian D-M, Cheng H-Y, Jiang M-M, Shen W-Z, Tang J-S, Yao X-S. Cardiac Glycosides from the Seeds of Thevetia peruviana. J Nat Prod. 2016 Jan 22;79(1):38–50. doi: 10.1021/acs.jnatprod.5b00611.

Ramos-Silva A, Tavares-Carreón F, Figueroa M, De la Torre-Zavala S, Gastelum-Arellanez A, Rodríguez-García A, et al. Anticancer potential of Thevetia peruviana fruit methanolic extract. BMC Complement Altern Med. 2017 Dec 2;17(1):241. doi: 10.1186/s12906-017-1727-y.

Shaker B, Ahmad S, Lee J, Jung C, Na D. In silico methods and tools for drug discovery. Comput Biol Med. 2021 Oct;137:104851. doi: 10.1016/j.compbiomed.2021.104851.

Vardhan S, Sahoo SK. In silico ADMET and molecular docking study on searching potential inhibitors from limonoids and triterpenoids for COVID-19. Comput Biol Med. 2020 Sep;124:103936. doi: 10.1016/j.compbiomed.2020.103936.

Guan L, Yang H, Cai Y, Sun L, Di P, Li W, et al. ADMET-score – a comprehensive scoring function for evaluation of chemical drug-likeness. Medchemcomm. 2019;10(1):148–57. doi: 10.1039/C8MD00472B

Jordan A, Hadfield JA, Lawrence NJ, McGown AT. Tubulin as a target for anticancer drugs: Agents which interact with the mitotic spindle. Med Res Rev. 1998 Jul;18(4):259–96. doi: 10.1002/(SICI)1098-1128(199807)18:4<259::AID-MED3>3.0.CO;2-U.

Friesen DE, Barakat KH, Semenchenko V, Perez‐Pineiro R, Fenske BW, Mane J, et al. Discovery of Small Molecule Inhibitors that Interact with γ‐Tubulin. Chem Biol Drug Des. 2012 May 15;79(5):639–52. doi: 10.1111/j.1747-0285.2012.01340.x.

Long J, Ouyang JC, Luo YH, Wu QJ, Liao XT, Chen Z Le, et al. Three new cardenolides from the fruits of Cascabela thevetia (L.) Lippold and their cytotoxic activities. Nat Prod Res. 2022;0(0):1–9. doi: 10.1080/14786419.2022.2113876. Cited: in: : PMID: 35983797.

Rathod S, Bhande D, Pawar S, Gumphalwad K, Choudhari P, More H. Identification of Potential Hits against Fungal Lysine Deacetylase Rpd3 via Molecular Docking, Molecular Dynamics Simulation, DFT, In-Silico ADMET and Drug-Likeness Assessment. Chem Africa. 2024 Mar 23;7(2):1151–64. doi: 10.1007/s42250-023-00766-5.

Butt SS, Badshah Y, Shabbir M, Rafiq M. Molecular Docking Using Chimera and Autodock Vina Software for Nonbioinformaticians. JMIR Bioinforma Biotechnol. 2020 Jun 19;1(1):e14232. doi: 10.2196/14232

Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017 Mar 3;7(1):42717. doi: 10.1038/srep42717.

Rashmi D. In-vitroADME studies of TUG-891, a GPR-120 inhibitor using Swiss ADME predictor. J Drug Deliv Ther. 2018;8(6):124–8.

Daina A, Zoete V. A BOILED‐Egg To Predict Gastrointestinal Absorption and Brain Penetration of Small Molecules. ChemMedChem. 2016 Jun 6;11(11):1117–21. doi: 10.1002/cmdc.201600182.

Sharma G, Kumar N, Sharma CS, Mishra SS. In silico guided screening of active components of C. lanceolata as 3-chymotrypsin-like protease inhibitors of novel coronavirus. 3 Biotech. 2023 Oct 31;13(10):324. doi: 10.1007/s13205-023-03745-2.

Abdelall EKA, Kamel GM. Synthesis of new thiazolo-celecoxib analogues as dual cyclooxygenase-2/15-lipoxygenase inhibitors: Determination of regio-specific different pyrazole cyclization by 2D NMR. Eur J Med Chem. 2016 Aug;118:250–8. doi: 10.1016/j.ejmech.2016.04.049.

Singh DB, Gupta MK, Singh DV, Singh SK, Misra K. Docking and in silico ADMET studies of noraristeromycin, curcumin and its derivatives with Plasmodium falciparum SAH hydrolase: A molecular drug target against malaria. Interdiscip Sci Comput Life Sci. 2013 Mar 19;5(1):1–12. doi: 10.1007/s12539-013-0147-z.

Published

30-09-2024
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How to Cite

“In Silico Pharmacokinetic, Molecular Docking and Molecular Dynamics Simulation Studies of Phytochemicals Isolated from Cascabela Thevetia As Potential Anticancer Agents”. International Journal of Pharmaceutical Sciences and Drug Research, vol. 16, no. 5, Sept. 2024, pp. 757-63, https://doi.org/10.25004/IJPSDR.2024.160502.

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Research Article

How to Cite

“In Silico Pharmacokinetic, Molecular Docking and Molecular Dynamics Simulation Studies of Phytochemicals Isolated from Cascabela Thevetia As Potential Anticancer Agents”. International Journal of Pharmaceutical Sciences and Drug Research, vol. 16, no. 5, Sept. 2024, pp. 757-63, https://doi.org/10.25004/IJPSDR.2024.160502.