{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T19:59:47Z","timestamp":1787169587644,"version":"build-2736575974"},"reference-count":45,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,5,18]],"date-time":"2023-05-18T00:00:00Z","timestamp":1684368000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSS Academy of Higher Education &amp; Research, Mysore"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Cancer is a condition marked by abnormal cell proliferation that has the potential to invade or indicate other health issues. Human beings are affected by more than 100 different types of cancer. Some cancer promotes rapid cell proliferation, whereas others cause cells to divide and develop more slowly. Some cancers, such as leukemia, produce visible tumors, while others, such as breast cancer, do not. In this work, in silico investigations were carried out to investigate the binding mechanisms of four major analogs, which are marine sesquiterpene, sesquiterpene lactone, heteroaromatic chalcones, and benzothiophene against the target estrogen receptor-\u03b1 for targeting breast cancer using Schr\u00f6dinger suite 2021-4. The Glide module handled the molecular docking experiments, the QikProp module handled the ADMET screening, and the Prime MM-GB\/SA module determined the binding energy of the ligands. The benzothiophene analog BT_ER_15f (G-score \u221215.922 Kcal\/mol) showed the best binding activity against the target protein estrogen receptor-\u03b1 when compared with the standard drug tamoxifen which has a docking score of \u221213.560 Kcal\/mol. TRP383 (tryptophan) has the highest interaction time with the ligand, and hence it could act for a long time. Based on in silico investigations, the benzothiophene analog BT_ER_15f significantly binds with the active site of the target protein estrogen receptor-\u03b1. Similar to the outcomes of molecular docking, the target and ligand complex interaction motif established a high affinity of lead candidates in a dynamic system. This study shows that estrogen receptor-\u03b1 targets inhibitors with better potential and low toxicity when compared to the existing market drugs, which can be made from a benzothiophene derivative. It may result in considerable activity and be applied to more research on breast cancer.<\/jats:p>","DOI":"10.3390\/molecules28104175","type":"journal-article","created":{"date-parts":[[2023,5,19]],"date-time":"2023-05-19T00:55:29Z","timestamp":1684457729000},"page":"4175","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["In Silico Drug Design of Anti-Breast Cancer Agents"],"prefix":"10.3390","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3382-4316","authenticated-orcid":false,"given":"Kalirajan","family":"Rajagopal","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, The Nilgiris, Ooty 643001, Tamilnadu, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6422-8798","authenticated-orcid":false,"given":"Anandarajagopal","family":"Kalusalingam","sequence":"additional","affiliation":[{"name":"Centre of Excellence for Pharmaceutical Sciences, School of Pharmacy, KPJ Healthcare University College, Nilai 71700, Negeri Sembilan, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anubhav Raj","family":"Bharathidasan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, The Nilgiris, Ooty 643001, Tamilnadu, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aadarsh","family":"Sivaprakash","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, The Nilgiris, Ooty 643001, Tamilnadu, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krutheesh","family":"Shanmugam","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, The Nilgiris, Ooty 643001, Tamilnadu, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monall","family":"Sundaramoorthy","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, The Nilgiris, Ooty 643001, Tamilnadu, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gowramma","family":"Byran","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, The Nilgiris, Ooty 643001, Tamilnadu, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.gendis.2018.05.001","article-title":"Breast cancer development and progression: Risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis","volume":"5","author":"Feng","year":"2018","journal-title":"Genes Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1002\/ca.22167","article-title":"The adolescent female: Breast and reproductive embryology and anatomy","volume":"26","author":"Lemaine","year":"2013","journal-title":"Clin. Anat."},{"key":"ref_3","unstructured":"Bisoyi, P. (2022). Understanding Cancer, Elsevier. Available online: https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/B9780323998833000111."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/s41568-019-0221-x","article-title":"Fluids and their mechanics in tumour transit: Shaping metastasis","volume":"20","author":"Follain","year":"2020","journal-title":"Nat. Rev. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"484","DOI":"10.3389\/fphar.2019.00484","article-title":"Cervical Cancer, Different Treatments and Importance of Bile Acids as Therapeutic Agents in This Disease","volume":"10","author":"Mikov","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"524","DOI":"10.3322\/caac.21754","article-title":"Breast Cancer Statistics, 2022","volume":"72","author":"Giaquinto","year":"2022","journal-title":"CA Cancer J. Clin."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1200\/GO.20.00122","article-title":"Cancer Statistics, 2020: Report From National Cancer Registry Programme, India","volume":"6","author":"Mathur","year":"2020","journal-title":"JCO Glob. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1007\/s11030-020-10133-y","article-title":"Most recent strategies targeting estrogen receptor alpha for the treatment of breast cancer","volume":"25","author":"Kumar","year":"2021","journal-title":"Mol. Divers."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/clpt.2010.226","article-title":"Estrogen Receptors: Therapies Targeted to Receptor Subtypes","volume":"89","author":"Nilsson","year":"2011","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/S0039-128X(03)00096-5","article-title":"Inhibition of aromatase: Insights from recent studies","volume":"68","author":"Santen","year":"2003","journal-title":"Steroids"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"7575","DOI":"10.1021\/acs.jmedchem.1c00280","article-title":"Dynamics-Based Discovery of Novel, Potent Benzoic Acid Derivatives as Orally Bioavailable Selective Estrogen Receptor Degraders for ER\u03b1+ Breast Cancer","volume":"64","author":"Zhang","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4883","DOI":"10.1021\/acs.jmedchem.5b00760","article-title":"Oral Selective Estrogen Receptor Downregulators (SERDs), a Breakthrough Endocrine Therapy for Breast Cancer","volume":"58","author":"McDonnell","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"489","DOI":"10.3816\/CBC.2010.n.065","article-title":"CLEOPATRA: A Phase III Evaluation of Pertuzumab and Trastuzumab for HER2-Positive Metastatic Breast Cancer","volume":"10","author":"Baselga","year":"2010","journal-title":"Clin. Breast Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s40487-017-0046-2","article-title":"A Review of Fulvestrant in Breast Cancer","volume":"5","author":"Nathan","year":"2017","journal-title":"Oncol. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.steroids.2014.06.012","article-title":"Estrogen receptors alpha (ER\u03b1) and beta (ER\u03b2): Subtype-selective ligands and clinical potential","volume":"90","author":"Paterni","year":"2014","journal-title":"Steroids"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1124\/pr.58.4.8","article-title":"International Union of Pharmacology. LXIV. Estrogen Receptors","volume":"58","author":"Cavailles","year":"2006","journal-title":"Pharmacol. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5551","DOI":"10.1080\/07391102.2020.1798285","article-title":"Identification of some novel oxazine substituted 9-anilinoacridines as SARS-CoV-2 inhibitors for COVID-19 by molecular docking, free energy calculation and molecular dynamics studies","volume":"39","author":"Rajagopal","year":"2021","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1007\/978-1-60761-839-3_11","article-title":"Pharmacophore-Based Virtual Screening","volume":"Volume 672","author":"Bajorath","year":"2010","journal-title":"Chemoinformatics and Computational Chemical Biology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1590","DOI":"10.1021\/ci900049e","article-title":"Consensus Superiority of the Pharmacophore-Based Alignment, Over Maximum Common Substructure (MCS): 3D-QSAR Studies on Carbamates as Acetylcholinesterase Inhibitors","volume":"49","author":"Chaudhaery","year":"2009","journal-title":"J. Chem. Inf. Model."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e05641","DOI":"10.1016\/j.heliyon.2020.e05641","article-title":"Molecular docking, molecular dynamics, and in vitro studies reveal the potential of angiotensin II receptor blockers to inhibit the COVID-19 main protease","volume":"6","author":"Alnajjar","year":"2020","journal-title":"Heliyon"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"114081","DOI":"10.1016\/j.ejmech.2021.114081","article-title":"Design and synthesis of marine sesterterpene analogues as novel estrogen receptor \u03b1 degraders for breast cancer treatment","volume":"229","author":"Liang","year":"2022","journal-title":"Eur. J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1016\/j.molonc.2016.03.002","article-title":"Novel sesquiterpene lactone analogues as potent anti-breast cancer agents","volume":"10","author":"Chen","year":"2016","journal-title":"Mol. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"239","DOI":"10.2174\/1568011053765976","article-title":"Anti-Cancer Potential of Sesquiterpene Lactones: Bioactivity and Molecular Mechanisms","volume":"5","author":"Zhang","year":"2005","journal-title":"Curr. Med. Chem.-Anti-Cancer Agents"},{"key":"ref_24","first-page":"27","article-title":"Synthesis and biological evaluation of some heterocyclic derivatives of chalcones","volume":"1","author":"Kalirajan","year":"2009","journal-title":"Int. J. Chem. Tech. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5921","DOI":"10.1016\/j.bmc.2016.09.051","article-title":"Synthesis and topoisomerases inhibitory activity of heteroaromatic chalcones","volume":"24","author":"Jeon","year":"2016","journal-title":"Bioorg. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"116395","DOI":"10.1016\/j.bmc.2021.116395","article-title":"Benzothiophene derivatives as selective estrogen receptor covalent antagonists: Design, synthesis and anti-ER\u03b1 activities","volume":"47","author":"Bai","year":"2021","journal-title":"Bioorg. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"7278731","DOI":"10.1155\/2022\/7278731","article-title":"Structure-Based In Silico Investigation of Agonists for Proteins Involved in Breast Cancer","volume":"2022","author":"Roy","year":"2022","journal-title":"Evid.-Based Complement. Alternat. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s43088-020-00059-7","article-title":"In silico molecular docking studies and MM\/GBSA analysis of coumarin-carbonodithioate hybrid derivatives divulge the anticancer potential against breast cancer","volume":"9","author":"Pattar","year":"2020","journal-title":"Beni-Suef Univ. J. Basic Appl. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/prot.21082","article-title":"Protein-ligand docking: Current status and future challenges. Proteins Struct","volume":"65","author":"Sousa","year":"2006","journal-title":"Funct. Bioinforma."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4759","DOI":"10.1021\/jm001044l","article-title":"Protein-Based Virtual Screening of Chemical Databases. 1. Evaluation of Different Docking\/Scoring Combinations","volume":"43","author":"Bissantz","year":"2000","journal-title":"J. Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6668","DOI":"10.33263\/BRIAC125.66686685","article-title":"Anti-Cancer, Anti-Osteoporosis, and Molecular Docking Studies of Novel Chalcone and Epoxy Chalcone","volume":"12","author":"Hussein","year":"2021","journal-title":"Biointerface Res. Appl. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1080\/17460441.2021.1942836","article-title":"What is the current value of MM\/PBSA and MM\/GBSA methods in drug discovery?","volume":"16","author":"Tuccinardi","year":"2021","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1006\/jmbi.2000.4057","article-title":"Free energy calculations on dimer stability of the HIV protease using molecular dynamics and a continuum solvent model","volume":"303","author":"Wang","year":"2000","journal-title":"J. Mol. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"529","DOI":"10.52711\/0974-360X.2023.00090","article-title":"COVID-19 Activity of Some 9-Anilinoacridines substituted with Pyrazole against SARS CoV2 Main Protease: An In-silico Approach","volume":"16","author":"Rajagopal","year":"2023","journal-title":"Res. J. Pharm. Technol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"9478","DOI":"10.1021\/acs.chemrev.9b00055","article-title":"End-Point Binding Free Energy Calculation with MM\/PBSA and MM\/GBSA: Strategies and Applications in Drug Design","volume":"119","author":"Wang","year":"2019","journal-title":"Chem. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Etti, I., Abdullah, R., Hashim, N., Kadir, A., Abdul, A., Etti, C., Malami, I., Waziri, P., and How, C. (2016). Artonin E and Structural Analogs from Artocarpus Species Abrogates Estrogen Receptor Signaling in Breast Cancer. Molecules, 21.","DOI":"10.3390\/molecules21070839"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Benfenati, E. (2016). In Silico Methods for Predicting Drug Toxicity, Springer. Methods in Molecular Biology.","DOI":"10.1007\/978-1-4939-3609-0"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.jsbmb.2013.04.009","article-title":"In silico methods in the discovery of endocrine disrupting chemicals","volume":"137","author":"Vuorinen","year":"2013","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1016\/j.drudis.2010.03.013","article-title":"Pharmacophore modeling and applications in drug discovery: Challenges and recent advances","volume":"15","author":"Yang","year":"2010","journal-title":"Drug Discov. Today"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e221","DOI":"10.1016\/j.ddtec.2010.11.004","article-title":"Strategies for 3D pharmacophore-based virtual screening","volume":"7","author":"Seidel","year":"2010","journal-title":"Drug Discov. Today Technol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4397","DOI":"10.2147\/DDDT.S84052","article-title":"High-throughput virtual screening with e-pharmacophore and molecular simulations study in the designing of pancreatic lipase inhibitors","volume":"9","author":"Veeramachaneni","year":"2015","journal-title":"Drug Des. Devel. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4991","DOI":"10.1007\/s00044-014-1072-3","article-title":"Quantitative structure\u2013activity relationship (QSAR) studies as strategic approach in drug discovery","volume":"23","author":"Patel","year":"2014","journal-title":"Med. Chem. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"921","DOI":"10.4172\/pharmaceutical-sciences.1000439","article-title":"Synthesis, Characterization and Antitumour Activity of Some Novel Oxazine Substituted 9-Anilinoacridines and their 3D-QSAR Studies","volume":"80","author":"Kalirajan","year":"2018","journal-title":"Indian J. Pharm. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1021\/cr040426m","article-title":"Molecular Dynamics: Survey of Methods for Simulating the Activity of Proteins","volume":"106","author":"Adcock","year":"2006","journal-title":"Chem. Rev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1021\/ct900587b","article-title":"Prediction of Absolute Solvation Free Energies using Molecular Dynamics Free Energy Perturbation and the OPLS Force Field","volume":"6","author":"Shivakumar","year":"2010","journal-title":"J. Chem. Theory Comput."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/10\/4175\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:38:00Z","timestamp":1760125080000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/10\/4175"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,18]]},"references-count":45,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["molecules28104175"],"URL":"https:\/\/doi.org\/10.3390\/molecules28104175","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,18]]}}}