Assessing the Specificity of Paclitaxel towards the Marker Proteins of Breast Cancer Using In silico Molecular Docking Study

Main Article Content

V. Senthil Kumar
T. V. Ajay Kumar
V. Parthasarathy


Breast cancer is highly prevalent next to lung cancer. Breast cancer occurs as a result of mutation in the genes like proto-oncogenes as well as tumor suppressor genes in a single clone of cells in the ductal and glandular regions of the breast. The drugs used to prevent breast cancer are Raloxifene hydrochloride and Tamoxifen citrate. The drugs used to treat breast cancer are Abemaciclib, Paclitaxel, Everolimus, Imatinib, Alpelisib, Anastrozole. Although several drug molecules had been developed, their specificity towards the potential breast cancer specific marker proteins such as activated threonine kinase 2/Protein kinase B (AKT2), cell division protein kinase 6 (CDK6), estrogen receptor (ER), human epidermal growth factor receptor type 2 (HER2), and poly ADP ribose polymerase1 (PARP1) need to be studied in silico. The present study was undertaken 1) to assess the specificity of paclitaxel towards the breast cancer specific marker proteins using molecular docking analysis and 2) to identify various physico-chemical properties of drug molecules including absorption, distribution, metabolism and excretion (ADME). The interaction between paclitaxel and the target proteins of breast cancer was analyzed using the Schrodinger Maestro Ver.2018.4. The results of the present study reveal that paclitaxel shows good binding interactions with the target proteins in the following order, ER > PARP1 > AKT2 >CDK6 > HER2. Among the five proteins, ER and PARP1 showed good binding interactions as compared to AKT2, CDK6 and HER2 proteins. The ADME properties of paclitaxel were predicted using QikProp module of Schrodinger Maestro version 2018.4. The present study warrant further studies which helps in the development of potent anticancer drug to treat breast cancer.

Cancer, breast cancer, paclitaxel, AKT2, CDK6, ER, HER2, PARP1, ADME, Schrodinger, QikProp.

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How to Cite
Kumar, V. S., Kumar, T. V. A., & Parthasarathy, V. (2020). Assessing the Specificity of Paclitaxel towards the Marker Proteins of Breast Cancer Using In silico Molecular Docking Study. Journal of Pharmaceutical Research International, 32(24), 64-73.
Original Research Article


Agha BM, Ahmadi F, Mohammadi E, Hagizadeh E, Varvarani A. Physical, emotional and social dimension of quality of life among breast cancer women under chemotherapy. Iranian Journal of Nursing Research. 2007;1(3):55-65.

Maliheh P, Maryam H, Abbas A, Peyman J, Mohammad S, Tahereh D, et al. Does a rehabilitation program improve quality of life in breast cancer patients?. Payesh. 2010;9(1):61-68.

Roses DF. Breast cancer. 2nd ed. Elsevier Inc: Philadelphia, PA; 2005.

Rebecca LS, Kimberly DM, Ahmedin J. Cancer statistics. CA: A Cancer Journal for Clinicians. ACS Journals. 2020;7(1):7-30. DOI: 10.3322/caac.21590

Anonymous. American cancer society: Cancer facts & figures 2020, Atlanta; 2020. Available: Accessed 23 August 2020.

Anonymous. About cancer: Cancer treatment, National Cancer Institute.; 2020. Available: Accessed 23 August 2020.

Anonymous. Understanding targeted therapy: How cancer is treated, editorial board, 2020. Available: procedures/what-are-targeted-therapies-cancer-treatment Accessed 25 August 2020.

Wani MC, Taylor HL, Wall ME, Coggon P, Mcphail AT. Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J Am Chem Soc. 1985; 88:2325-2327. DOI: 10.1021/ja00738a045

Kim S, Chen J, Cheng T, Gindulyte A, He J, He S, et al. PubChem update: Improved access to chemical data. Nucleic Acids Research. 2019;47(1):1102-1109. DOI: 10.1093/nar/gky1033

Anonymous. Schrödinger release. Maestro, Schrödinger, LLC. New York, NY, 2018;4.

Anonymous. Schrödinger release. LigPrep, Schrödinger, LLC. New York, NY. 2018-4.

Ajay-Kumar TV, Athavan AAS, Loganathan C, Saravanan K, Kabilan S, Parthasarathy V. Design, 3D QSAR modeling and docking of TGF-β type I inhibitors to target cancer. Comput Biol Chem. 2018;76:232-244. DOI: 10.1016/j.compbiolchem.2018.07.011

Heerding DA, Rhodes N, Leber JD, et al. Identification of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a novel inhibitor of AKT kinase. J Med Chem. 2008;51(18):5663-5679. DOI: 10.1021/jm8004527

Cho YS, Angove H, Brain C, et al. Fragment-based discovery of 7-Azabenzimidazoles as potent, highly selective, and orally active CDK4/6 inhibitors. ACS Med Chem Lett. 2012; 3(6):445-449. DOI:10.1021/ml200241a

Shiau AK, Barstad D, Loria PM, et al. The structural basis of estrogen receptor/ coactivator recognition and the antagonism of this interaction by tamoxifen. Cell. 1998;95(7):927-937. DOI: 10.1016/S0092-8674(00)81717-1

Aertgeerts K, Skene R, Yano J, et al. Structural analysis of the mechanism of inhibition and allosteric activation of the kinase domain of HER2 protein. J Biol Chem. 2011;286(21):18756-18765. DOI: 10.1074/jbc.M110.206193

Park CH. PARP complexed with A620223. In Press; 2008. DOI: 10.2210/pdb2RCW/pdb

Anonymous. Schrodinger release 2018-4: Protein Preparation Wizard; Epik, Schrödinger, LLC, New York. NY. Impact, Schrödinger, LLC, New York, NY, 2018; Prime, Schrödinger, LLC, New York, NY, 2018.

Anonymous. Schrodinger Release. Glide, Schrödinger, LLC, New York, NY. 2018;4.

Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren T, et al. Extra precision glide: Docking and scoring incorporating a model of hdrophobic enclosure for protein-ligand complexes. J. Med. Chem. 2006;49:6177-6196. DOI: 10.1021/jm051256o

Ajay Kumar TV, Kabilan S, Parthasarathy V. Discovery of inhibitors of TGF-β Type I receptor using QSAR, pharmacophore modelling and toxicity assessment techniques/study to target Cancer. Der Pharma Chemica. 2016;8(22):17-21.

Tahlan S, Kumar S, Ramasamy K, et al. In-silico molecular design of heterocyclic benzimidazole scaffolds as prospective anticancer agents. BMC Chemistry. 2019; 13(1):90. DOI: 10.1186/s13065-019-0608-5

Anonymous. Schrödinger Release. QikProp, Schrödinger, LLC, New York. NY. 2018;4.

Lipinski CA. Lead and drug-like compounds: the rule-of-five revolution. Drug Discovery Today: Technologies. 2004;1(4):337-341. DOI: 10.1016/j.ddtec.2004.11.007

Pagadala NS, Syed K, Tuszynski J. Software for molecular docking: A review. Biophys Rev. 2017;9(2):91-102.

Kitchen DB, Decornez H, Furr JR, Bajorath J. Docking and scoring in virtual screening for drug discovery: Methods and applications. Nature Reviews Drug Discovery. 2004;3 (11):935–49. DOI: 10.1038/nrd1549

Hinz N, Jucker M. Distinct functions of AKT isoforms in breast cancer: A comprehensive review. Cell Commun Signal. 2019;17(1):154. DOI: 10.1186/s12964-019-0450-3

Chau NM, Ashcroft M. Akt2: A role in breast cancer metastasis. Breast Cancer Res. 2004;6(1):55-57. DOI: 10.1186/bcr739

Sofie N, Karoline K, Veronika S. The role of CDK6 in cancer. International Journal of Cancer. 2020:1-8. DOI: 10.1002/ijc.33054

Weaver BA. How Taxol/paclitaxel kills cancer cells. Mol Biol Cell. 2014;25:2677–81. DOI: 10.1091/mbc.E14-04-0916

Tadesse S, Yu M, Kumarasiri M, Le BT, Wang S. Targeting CDK6 in cancer: State of the art and new insights. Cell cycle. 2015;14(20):3220-3230. DOI: 10.1080/15384101.2015.1084445

Cortez V, Mann M, Brann DW, Vadlamudi RK. Extranuclear signaling by estrogen: role in breast cancer progression and metastasis. Minerva Ginecol. 2010; 62(6):573-583.

Mitri Z, Constantine T, Regan OR. The HER2 Receptor in Breast cancer: Pathophysiology, clinical use, and new advances in therapy. Chemother Res Pract. 2012;2012:743193. DOI: 10.1155/2012/743193

Ossovskaya V, Koo IC, Kaldjian EP, Alvares C, Sherman BM. Upregulation of poly (ADP-Ribose) Polymerase-1 (PARP1) in triple-negative breast cancer and other primary human tumor types. Genes Cancer. 2010;1(8):812-821. DOI: 10.1177/1947601910383418

Mori T, Kinoshita Y, Watanabe A, Yamaguchi T, et al. Retention of paclitaxel in cancer cells for 1 week in vivo and in vitro. Cancer Chemother. 2006;58(5):665-672

Chen K, Shi W. Autophagy regulates resistance of non-small cell lung cancer cells to paclitaxel. Tumor Biol. 2016;37: 10539-44.

DOI: 10.1007/s13277-016-4929-x

Zhang DS, Yang RH, Wang SX, Dong Z. Paclitaxel: New uses for an old drug. Drug Des Dev Ther. 2014;8:279-84. DOI: 10.2147/DDDT.S56801

Okomoto Y, Taguchi K, Sakuragi M, et al. Preparation, charecterization, and In vitro/In vivo evaluation of paclitaxel bound albumin-encapsulated liposomes for the treatment of pancreatic cancer. ACS omega. 2019;4(5):8693-8700.

Clark AS, McAndrew NP, Troxel A, Feldman M et al. Combination paclitaxel and palbociclib: Results of a phase I trial in advanced breast cancer. Clin Cancer Res. 2019;25(7):2072-2079.

Osma M, Elkady M. A prospective study to evaluate the effect of paclitaxel on cardiac ejection fraction. Breast Care (Basel). 2017;12(4):255-259.

Su M, Chen G, Lin J, et al. Paclitaxel-related dermatological problems: Not only alopecia occurs. Taiwanese Journal of Obstetrics and Gynecology. 2019;58(6): 877-879.

Bassyouni F, El Hefnawi M, El-Rashed A, Rehim MA. Molecular modeling and biological activities of new potent antimicrobial, antiinflammatory and anti-nociceptive of 5-nitro indoline-2-one derivatives. Drug Des. 2017;6(2):1-6.

Sharma D, Kumar S, Narasimhan B, Ramasamy K, Lim SM, Shah SAA, et al. 4-(4-Bromophenyl)-thiazol-2-amine derivatives: Synthesis, biological activity and molecular docking study with ADME profile. BMC Chem. 2019;13(60): 1-16.
DOI: 10.1186/s13065-019-0575-x