Design, Molecular Docking and Molecular Dynamic Simulation of New Heterocyclic Derivatives as Potential Anticancer Agents
DOI:
https://doi.org/10.54133/ajms.v7i1(Special).1033Keywords:
ADME, Anticancer activity, Benzothiophene, ERRγ inhibitors, Molecular dockingAbstract
Background: Despite significant progress in the development of anticancer medications, obstacles such as drug resistance, poor efficacy, and excessive toxicity have significantly impacted the daily lives of cancer patients. Consequently, the search for highly selective, effective, and non-toxic molecules remains a major challenge for cancer researchers. Objective: To utilize a computer program for evaluating new benzothiophene derivatives to investigate how they influence the estrogen-related receptor-gamma (ERRγ) active sites as anticancer agents. Methods: The molecular docking method used the Cambridge Crystallographic Data Centre's (CCDC) Genetic Optimization for Ligand Docking (GOLD) tool. We used the Desmond modules of the Schrodinger 2023 to perform MDS on the derivative with the highest docking score. The Swiss ADME server then assessed our drugs' pharmacokinetic profile, which included how well they crossed the blood-brain barrier (BBB), bound to P-gp, and were bioavailable. Results: The compounds were docked with the ERRγ crystal structure (2GPV) to assess their binding affinity to active sites. One of them earned a high score (102.62), and six compounds had a higher binding energy than the gold standard medication, tamoxifen. The molecular dynamic simulation analysis found that compound 1 closely matched the ERRγ based on RMSD and RMSF data. After examining the ADME study of practically active substances, they follow Lipinski's laws and other pharmacokinetic features. Conclusions: These chemicals have the potential to act as precursors in the development of new anticancer medicines.
Downloads
References
Bizuayehu HM, Dadi AF, Hassen TA, Ketema DB, Ahmed KY, Kassa ZY, et al. Global burden of 34 cancers among women in 2020 and projections to 2040: Population‐based data from 185 countries/territories. Int J Cancer. 2024;154(8):1377-1393. doi: 10.1002/ijc.34809.
Mamidala S, Mudigunda VS, Peddi SR, Bokara KK, Manga V, Vedula RR. Design and synthesis of new thiazoles by microwave-assisted method: evaluation as an anti-breast cancer agents and molecular docking studies. Synth Commun. 2020;50(16):2488-2501. doi: 10.6084/m9.figshare.12845036.v1.
Ahmad A. Current updates on trastuzumab resistance in HER2 overexpressing breast cancers. Breast cancer Metastasis and drug resistance. Cham. 2019:217-228. doi: 10.1007/978-3-030-20301-6_10.
Brufsky AM, Dickler MN. Estrogen receptor‐positive breast cancer: exploiting signaling pathways implicated in endocrine resistance. J Oncol. 2018;23(5):528-539. doi: 10.1634/theoncologist.2017-0423.
Lv W, Liu J, Lu D, Flockhart DA, Cushman M. Synthesis of mixed (E, Z)-,(E)-, and (Z)-norendoxifen with dual aromatase inhibitory and estrogen receptor modulatory activities. J Med Chem. 2013;56(11):4611-4618. doi: 10.1021/jm400364h.
Misawa A, Inoue S. Estrogen-related receptors in breast cancer and prostate cancer. Front. Endocrinol. 2015;6:141562. doi: 10.3389/fendo.2015.00083.
Kraus RJ, Ariazi EA, Farrell ML, Mertz JE. Estrogen-related receptor α1 actively antagonizes estrogen receptor-regulated transcription in MCF-7 mammary cells. JBC. 2002;277(27):24826-24834. doi: 10.1074/jbc.M202952200.
Stein RA, Gaillard S, McDonnell DP. Estrogen-related receptor alpha induces the expression of vascular endothelial growth factor in breast cancer cells. J Steroid Biochem Mol Biol. 2009;114(1-2):106-112. doi 10.1016/j.jsbmb.2009.02.010.
Suzuki T, Miki Y, Moriya T, Shimada N, Ishida T, Hirakawa H, et al. Estrogen-related receptor α in human breast carcinoma as a potent prognostic factor. Cancer Res. 2004;64(13):4670-4676. doi: 10.1158/0008-5472.CAN-04-0250.
Coward P, Lee D, Hull MV, Lehmann JM. 4-Hydroxytamoxifen binds to and deactivates the estrogen-related receptor γ. PNAS. 2001;98(15):8880-8884. doi: 10.1073/pnas.151244398.
Caciolla J, Bisi A, Belluti F, Rampa A, Gobbi S. Reconsidering aromatase for breast cancer treatment: new roles for an old target. Molecules. 2020;25(22):5351. doi: 10.3390/molecules25225351.
Alawad KM, Mahdi MF, Raauf AM. Molecular docking, synthesis, characterization and adme studies of some new five-member ring heterocyclic compounds with in vitro antiproliferative evaluation. J Hunan Univ Nat Sci. 2021;48(9).
Amer M, Mahdi MF, Khan AK, Raauf AMR. Design, molecular docking, synthesis, preliminary in silico ADME studies, and anti-inflammatory evaluation of new oxazole derivatives. J Pharm Negat Results. 2022:217-228.
Abdulredha FH, Mahdi MF, Khan AK. In silico molecular docking, ADME study and synthesis of new 1, 3-diazetidin-2-one derivatives with high anti-proliferative activity. F1000Research. 2023;12:1090. doi: 10.12688/f1000research.138510.1.
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;7(1):42717. doi: 10.1038/srep42717.
Zekri A, Harkati D, Kenouche S, Saleh BA. QSAR modeling, docking, ADME and reactivity of indazole derivatives as antagonizes of estrogen receptor alpha (ER-α) positive in breast cancer. J Mol Struct. 2020;1217:128442. doi: 10.1016/j.molstruc.2020.128442.
Chennai HY, Belaidi S, Bourougaa L, Ouassaf M, Sinha L, Samadi A, et al. Identification of potent acetylcholinesterase inhibitors as new candidates for Alzheimer disease via virtual Screening, Molecular Docking, Dynamic Simulation, and Molecular Mechanics–Poisson–boltzmann surface area calculations. Molecules. 2024;29(6):1232. doi: 10.3390/molecules29061232.
Agrawal K, Patel T, Thakur S, Patel K, Mittal S. Spectral investigations, DFT studies, ADME analysis, molecular docking of new piperidine derivatives with potential antimicrobial activity. J Sci Technol. 2023;16(35):2835-2844. doi: 10.17485/IJST/v16i35.389.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2024 Al-Rafidain Journal of Medical Sciences ( ISSN 2789-3219 )
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Published by Al-Rafidain University College. This is an open access journal issued under the CC BY-NC-SA 4.0 license (https://creativecommons.org/licenses/by-nc-sa/4.0/).