{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:19:08Z","timestamp":1785403148076,"version":"3.56.0"},"reference-count":33,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004442","name":"National Science Centre","doi-asserted-by":"publisher","award":["2019\/33\/B\/NZ7\/01608"],"award-info":[{"award-number":["2019\/33\/B\/NZ7\/01608"]}],"id":[{"id":"10.13039\/501100004442","id-type":"DOI","asserted-by":"publisher"}]},{"award":["2019\/33\/B\/NZ7\/01608"],"award-info":[{"award-number":["2019\/33\/B\/NZ7\/01608"]}],"id":[{"id":"https:\/\/ror.org\/03ha2q922","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Medical University of Lublin, Poland","award":["DS 15"],"award-info":[{"award-number":["DS 15"]}]},{"award":["DS 15"],"award-info":[{"award-number":["DS 15"]}],"id":[{"id":"https:\/\/ror.org\/016f61126","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Steroid sulfatase (STS) plays a crucial role in intratumoral estrogen biosynthesis and represents an attractive therapeutic target in estrogen receptor-positive breast cancer. In this study, a new series of potential STS inhibitors based on the quinone methide oxime scaffold, precisely 2-(4-hydroxyiminocyclohexa-2,5-dien-1-ylidene)-2-phenylacetonitrile framework, were designed and evaluated using an integrated in silico approach. A virtual library comprising 216 compounds (including syn\/anti isomers) was screened by molecular docking against the human STS crystal structure (PDB ID: 8EG3). The binding affinities ranged from \u22127.077 to \u22129.726 kcal\u00b7mol\u22121; however, only the best-performing compound 45-syn showed values comparable to those of the reference ligands. The top-ranked compound (45-syn) exhibited favorable interactions within the catalytic site, including polar contacts near the FGly\u2013Ca2+ region and extensive hydrophobic and \u03c0\u2013\u03c0 interactions in the adjacent pocket. Structure\u2013binding relationship analysis highlighted the importance of electron-withdrawing substituents at R1 and aromatic moieties at R2 for enhanced binding. Molecular dynamics simulations confirmed the stability of ligand\u2013STS complexes and demonstrated reduced flexibility compared to the apo form. Additionally, in silico ADMET predictions indicated generally favorable drug-like profiles for selected candidates. Overall, the results highlight computationally prioritized scaffolds that merit further synthesis and biological evaluation as potential STS inhibitors.<\/jats:p>","DOI":"10.3390\/molecules31152612","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T11:54:26Z","timestamp":1785153266000},"page":"2612","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["In Silico Design and Evaluation of Quinone Methide Oxime Derivatives as Potential Non-Covalent Steroid Sulfatase Inhibitors"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9306-7463","authenticated-orcid":false,"given":"Dmytro","family":"Khylyuk","sequence":"first","affiliation":[{"name":"Chair and Department of Organic Chemistry, Medical University of Lublin, ul. Chod\u017aki 4a, 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5571-1593","authenticated-orcid":false,"given":"Oleg M.","family":"Demchuk","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, The John Paul II Catholic University of Lublin, Konstantynow 1J, 20-708 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9892-437X","authenticated-orcid":false,"given":"Sergii","family":"Holota","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, 69 Pekarska St., 79010 Lviv, Ukraine"},{"name":"Molecular Design Center, Danylo Halytsky Lviv National Medical University, Pekarska 69, 79010 Lviv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dagmara","family":"Otto-\u015alusarczyk","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0181-3607","authenticated-orcid":false,"given":"Marta","family":"Struga","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franciszek","family":"Burdan","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, Medical University of Lublin, 4 Jaczewski Street, 20-090 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9816-1934","authenticated-orcid":false,"given":"Monika","family":"Wujec","sequence":"additional","affiliation":[{"name":"Chair and Department of Organic Chemistry, Medical University of Lublin, ul. Chod\u017aki 4a, 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"key":"ref_1","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Miziak, P., Baran, M., B\u0142aszczak, E., Przybyszewska-Podstawka, A., Ka\u0142afut, J., Smok-Kalwat, J., Dmoszy\u0144ska-Graniczka, M., Kie\u0142bus, M., and Stepulak, A. (2023). Estrogen Receptor Signaling in Breast Cancer. Cancers, 15.","DOI":"10.3390\/cancers15194689"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.mce.2017.11.010","article-title":"Extranuclear Signaling by Sex Steroid Receptors and Clinical Implications in Breast Cancer","volume":"466","author":"Boonyaratanakornkit","year":"2018","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1007\/s12282-025-01779-3","article-title":"Advances in the Intrinsic Signaling Pathway Interactions and Clinical Translation of HR+\/HER2+ Breast Cancer","volume":"32","author":"Li","year":"2025","journal-title":"Breast Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1038\/s41416-018-0221-8","article-title":"Hierarchical Clustering of Activated Proteins in the PI3K and MAPK Pathways in ER-Positive, HER2-Negative Breast Cancer with Potential Therapeutic Consequences","volume":"119","author":"Kruger","year":"2018","journal-title":"Br. J. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.1001\/jamaoncol.2016.1279","article-title":"Prevalence of ESR1 Mutations in Cell-Free DNA and Outcomes in Metastatic Breast Cancer: A secondary analysis of the BOLERO-2 clinical trial","volume":"2","author":"Chandarlapaty","year":"2016","journal-title":"JAMA Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1158\/0008-5472.CAN-21-2576","article-title":"Hotspot ESR1 Mutations Are Multimodal and Contextual Modulators of Breast Cancer Metastasis","volume":"82","author":"Li","year":"2022","journal-title":"Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Clusan, L., Ferri\u00e8re, F., Flouriot, G., and Pakdel, F. (2023). A Basic Review on Estrogen Receptor Signaling Pathways in Breast Cancer. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24076834"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1210\/er.2003-0037","article-title":"Hereditary Hormone Excess: Genes, Molecular Pathways, and Syndromes","volume":"26","author":"Marx","year":"2005","journal-title":"Endocr. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1530\/JOE-11-0266","article-title":"Steroid Sulfatase Inhibitors for Estrogen- and Androgen-Dependent Cancers","volume":"212","author":"Purohit","year":"2012","journal-title":"J. Endocrinol."},{"key":"ref_11","first-page":"27","article-title":"Steroid Metabolism in Breast Cancer","volume":"33","author":"Foster","year":"2008","journal-title":"Minerva Endocrinol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Ri\u017ener, T.L. (2016). The Important Roles of Steroid Sulfatase and Sulfotransferases in Gynecological Diseases. Front. Pharmacol., 7.","DOI":"10.3389\/fphar.2016.00030"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1042\/EBC20230096","article-title":"Steroid Sulfatase and Sulfotransferases in the Estrogen and Androgen Action of Gynecological Cancers: Current Status and Perspectives","volume":"68","author":"Gjorgoska","year":"2024","journal-title":"Essays Biochem."},{"key":"ref_14","first-page":"2762","article-title":"Estrogen Sulfotransferase and Steroid Sulfatase in Human Breast Carcinoma","volume":"63","author":"Suzuki","year":"2003","journal-title":"Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1007\/s00018-007-7175-y","article-title":"Human Sulfatases: A Structural Perspective to Catalysis","volume":"64","author":"Ghosh","year":"2007","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1021\/cb500897w","article-title":"Formylglycine, a Post-Translationally Generated Residue with Unique Catalytic Capabilities and Biotechnology Applications","volume":"10","author":"Appel","year":"2015","journal-title":"ACS Chem. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1210\/er.2004-0003","article-title":"Steroid Sulfatase: Molecular Biology, Regulation, and Inhibition","volume":"26","author":"Reed","year":"2005","journal-title":"Endocr. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"T233","DOI":"10.1530\/JME-18-0045","article-title":"SULFATION PATHWAYS: Steroid Sulphatase Inhibition via Aryl Sulphamates: Clinical Progress, Mechanism and Future Prospects","volume":"61","author":"Potter","year":"2018","journal-title":"J. Mol. Endocrinol."},{"key":"ref_19","unstructured":"Bertino, J.R. (2002). Encyclopedia of Cancer, Academic Press. [2nd ed.]."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.jsbmb.2011.02.002","article-title":"Steroid Sulfatase Inhibitors: Promising New Tools for Breast Cancer Therapy? J","volume":"125","author":"Geisler","year":"2011","journal-title":"Steroid Biochem. Mol. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3326","DOI":"10.1021\/acs.biochem.8b00315","article-title":"The Taxonomy of Covalent Inhibitors","volume":"57","author":"Tuley","year":"2018","journal-title":"Biochemistry"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Foster, P.A. (2021). Steroid Sulphatase and Its Inhibitors: Past, Present, and Future. Molecules, 26.","DOI":"10.3390\/molecules26102852"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1039\/D0MD00154F","article-title":"Covalent Inhibitors: A Rational Approach to Drug Discovery","volume":"11","author":"Sutanto","year":"2020","journal-title":"RSC Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1708","DOI":"10.1002\/cmdc.200800164","article-title":"Synthesis of Aromatase Inhibitors and Dual Aromatase Steroid Sulfatase Inhibitors by Linking an Arylsulfamate Motif to 4-(4H-1,2,4-triazol-4-ylamino)Benzonitrile: SAR, Crystal Structures, in Vitro and in Vivo Activities","volume":"3","author":"Bubert","year":"2008","journal-title":"ChemMedChem"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1002\/cmdc.201300015","article-title":"Synthesis and Structure\u2013Activity Relationship Studies of Derivatives of the Dual Aromatase\u2013Sulfatase Inhibitor 4-{[(4-Cyanophenyl)(4 H -1,2,4-triazol-4-yl)Amino]Methyl}phenyl Sulfamate","volume":"8","author":"Woo","year":"2013","journal-title":"ChemMedChem"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3891","DOI":"10.1021\/acs.jcim.1c00203","article-title":"AutoDock Vina 1.2.0: New Docking Methods, Expanded Force Field, and Python Bindings","volume":"61","author":"Eberhardt","year":"2021","journal-title":"J. Chem. Inf. Model."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1021\/ci800084x","article-title":"An Alternative Method for the Evaluation of Docking Performance: RSR vs RMSD","volume":"48","author":"Yusuf","year":"2008","journal-title":"J. Chem. Inf. Model."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"42717","DOI":"10.1038\/srep42717","article-title":"SwissADME: A Free Web Tool to Evaluate Pharmacokinetics, Drug-Likeness and Medicinal Chemistry Friendliness of Small Molecules","volume":"7","author":"Daina","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5681","DOI":"10.1016\/j.bmc.2015.07.019","article-title":"A-Ring Substituted 17\u03b2-Arylsulfonamides of 17\u03b2-Aminoestra-1,3,5(10)-Trien-3-Ol as Highly Potent Reversible Inhibitors of Steroid Sulfatase","volume":"23","author":"Mostafa","year":"2015","journal-title":"Bioorg. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1002\/jcc.20291","article-title":"GROMACS: Fast, Flexible, and Free","volume":"26","author":"Lindahl","year":"2005","journal-title":"J. Comput. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1002\/jcc.20035","article-title":"Development and Testing of a General Amber Force Field","volume":"25","author":"Wang","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1517\/17460441.2015.1032936","article-title":"The MM\/PBSA and MM\/GBSA Methods to Estimate Ligand-Binding Affinities","volume":"10","author":"Genheden","year":"2015","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"W53","DOI":"10.1093\/nar\/gku401","article-title":"ProTox: A Web Server for the in Silico Prediction of Rodent Oral Toxicity","volume":"42","author":"Drwal","year":"2014","journal-title":"Nucleic Acids Res."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/15\/2612\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T11:54:34Z","timestamp":1785153274000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/15\/2612"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,27]]},"references-count":33,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["molecules31152612"],"URL":"https:\/\/doi.org\/10.3390\/molecules31152612","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,27]]}}}