Computational Screening and Molecular Docking of Compounds from Traditional Chinese Medicine (TCM) by Targeting DNA Topoisomerase I to Design Potential Anticancer Drugs

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2024 Sep 12

PMID 39264927

Authors

Mst Sharmin Sultana Shimu

Affiliations

Soon will be listed here.

Abstract

Each year thousands of people suffer across the globe due to higher cancer incidence and mortality rates. Additionally, the treatment option for cancer patients is also costly, and often cancer drugs suffer from lower efficacy with more side effects. The DNA topoisomerase can function as an established cancer target because Human Topoisomerase (Top1) regulates genetic transcription during the post-mitotic phase and plays a critical role in DNA supercoiling during replication and repair. Therefore, during drug therapy, blocking the Top1 may be crucial for inhibiting the proliferation of cancer cells. Here, the TCM (traditional Chinese medicine) compounds have been screened through the virtual screening. The Chinese medicine library's virtual screening process made it possible to narrow down the compound list to 29 compounds based on binding energy (-7.1 to -9.3Kcal/mol), while following Lipniski filtering, MM/PB (GB) SA filtering was used to screen the remaining 22 compounds and the top four compounds were chosen based on binding free energy. Here, the four compounds; CID-65752 (T2972: Rutaecarpine), CID-5271805 (T4S2126: Ginkgetin), CID-9817839 (T2S2335: Dehydroevodiamine) and CID-51106 (T3054: Daurisoline) had comparatively higher binding energy of -8.2, -8.5, -8.3 and -8.2 respectively during molecular docking than other compounds. Among these four compounds, no toxic profile of the two screened compounds; CID-5271805 and CID-9817839 was found in ADMET filtering. Moreover, the SASA (solvent accessible surface area), Rg (radius of gyrations), RMSD (root mean square deviation), and RMSF (root mean square fluctuation) profile of the drug-protein complex reveals the stability and rigidity of the compounds in molecular dynamics simulation study. However, these studies need to be validated in experimental approaches to develop more potent and effective cancer drugs.

Citing Articles

Exploring Herbal Compounds as Targeted Therapies for Breast Cancer: Insights from Network Pharmacology, Molecular Docking, MD Simulation, ADME-Toxicity and DFT Profiles.

Zhang H Iran J Pharm Res. 2025; 23(1):e153579.

PMID: 40066125 PMC: 11892757. DOI: 10.5812/ijpr-153579.

In Silico Discovery of a Novel PI3Kδ Inhibitor Incorporating 3,5,7-Trihydroxychroman-4-one Targeting Diffuse Large B-Cell Lymphoma.

Jia W, Liu J, Cheng X, Li X, Ma Y Int J Mol Sci. 2024; 25(20).

PMID: 39457034 PMC: 11508633. DOI: 10.3390/ijms252011250.

References

Brangi M, Litman T, Ciotti M, Nishiyama K, Kohlhagen G, Takimoto C . Camptothecin resistance: role of the ATP-binding cassette (ABC), mitoxantrone-resistance half-transporter (MXR), and potential for glucuronidation in MXR-expressing cells. Cancer Res. 1999; 59(23):5938-46. View

Wang D, Zhang W, Zhang X, Li M, Wu Q, Li X . Daurisoline suppresses esophageal squamous cell carcinoma growth in vitro and in vivo by targeting MEK1/2 kinase. Mol Carcinog. 2023; 62(4):517-531. DOI: 10.1002/mc.23503. View

Wang Z, Pan H, Sun H, Kang Y, Liu H, Cao D . fastDRH: a webserver to predict and analyze protein-ligand complexes based on molecular docking and MM/PB(GB)SA computation. Brief Bioinform. 2022; 23(5). DOI: 10.1093/bib/bbac201. View

Pommier Y . DNA topoisomerase I inhibitors: chemistry, biology, and interfacial inhibition. Chem Rev. 2009; 109(7):2894-902. PMC: 2707511. DOI: 10.1021/cr900097c. View

Goodsell D, Zardecki C, Di Costanzo L, Duarte J, Hudson B, Persikova I . RCSB Protein Data Bank: Enabling biomedical research and drug discovery. Protein Sci. 2019; 29(1):52-65. PMC: 6933845. DOI: 10.1002/pro.3730. View

Atun R, Bhakta N, Denburg A, Frazier A, Friedrich P, Gupta S . Sustainable care for children with cancer: a Lancet Oncology Commission. Lancet Oncol. 2020; 21(4):e185-e224. DOI: 10.1016/S1470-2045(20)30022-X. View

Kim H, Ryu J, Lee J, Lee S . A systems approach to traditional oriental medicine. Nat Biotechnol. 2015; 33(3):264-8. DOI: 10.1038/nbt.3167. View

Chillemi G, Redinbo M, Bruselles A, Desideri A . Role of the linker domain and the 203-214 N-terminal residues in the human topoisomerase I DNA complex dynamics. Biophys J. 2004; 87(6):4087-97. PMC: 1304917. DOI: 10.1529/biophysj.104.044925. View

Liu W, Furuta E, Shindo K, Watabe M, Xing F, Pandey P . Cacalol, a natural sesquiterpene, induces apoptosis in breast cancer cells by modulating Akt-SREBP-FAS signaling pathway. Breast Cancer Res Treat. 2010; 128(1):57-68. DOI: 10.1007/s10549-010-1076-8. View

10.

Shimu M, Mahmud S, Tallei T, Sami S, Adam A, Acharjee U . Phytochemical Compound Screening to Identify Novel Small Molecules against Dengue Virus: A Docking and Dynamics Study. Molecules. 2022; 27(3). PMC: 8840231. DOI: 10.3390/molecules27030653. View

11.

Jayabal D, Jayanthi S, Thirumalaisamy R, Shimu M . Molecular insights of anti-diabetic compounds and its hyaluronic acid conjugates against aldose reductase enzyme through molecular modeling and simulations study-a novel treatment option for inflammatory diabetes. J Mol Model. 2023; 29(8):238. DOI: 10.1007/s00894-023-05616-2. View

12.

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

13.

Liu Y, Grimm M, Dai W, Hou M, Xiao Z, Cao Y . CB-Dock: a web server for cavity detection-guided protein-ligand blind docking. Acta Pharmacol Sin. 2019; 41(1):138-144. PMC: 7471403. DOI: 10.1038/s41401-019-0228-6. View

14.

Liu Y, Zheng C, Huang Y, He M, Xu W, Li B . Molecular mechanisms of chemo- and radiotherapy resistance and the potential implications for cancer treatment. MedComm (2020). 2021; 2(3):315-340. PMC: 8554658. DOI: 10.1002/mco2.55. View

15.

Alherz F, Negm W, El-Masry T, Elmorshedy K, El-Kadem A . The potential beneficial role of Ginkgetin in doxorubicin-induced hepatotoxicity: Elucidating the underlying claim. Biomed Pharmacother. 2023; 165:115010. DOI: 10.1016/j.biopha.2023.115010. View

16.

Eberhardt J, Santos-Martins D, Tillack A, Forli S . AutoDock Vina 1.2.0: New Docking Methods, Expanded Force Field, and Python Bindings. J Chem Inf Model. 2021; 61(8):3891-3898. PMC: 10683950. DOI: 10.1021/acs.jcim.1c00203. View

17.

Jeon H, Han Y, Mun J, Yoon D, Lee Y, Kee J . Dehydroevodiamine inhibits lung metastasis by suppressing survival and metastatic abilities of colorectal cancer cells. Phytomedicine. 2021; 96:153809. DOI: 10.1016/j.phymed.2021.153809. View

18.

Meng L, Liao Z, Pommier Y . Non-camptothecin DNA topoisomerase I inhibitors in cancer therapy. Curr Top Med Chem. 2003; 3(3):305-20. DOI: 10.2174/1568026033452546. View

19.

Pires D, Blundell T, Ascher D . pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures. J Med Chem. 2015; 58(9):4066-72. PMC: 4434528. DOI: 10.1021/acs.jmedchem.5b00104. View

20.

Wang J . Cellular roles of DNA topoisomerases: a molecular perspective. Nat Rev Mol Cell Biol. 2002; 3(6):430-40. DOI: 10.1038/nrm831. View