{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T13:54:24Z","timestamp":1791122064068,"version":"4.1.0"},"reference-count":79,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T00:00:00Z","timestamp":1780012800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T00:00:00Z","timestamp":1780012800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Universidade Federal Do Par\u00e1"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Divers"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Tyrosinase (TYR) is a copper-containing metalloenzyme involved in melanin biosynthesis and is an important target in the development of treatments for hyperpigmentation disorders, including melasma, post-inflammatory hyperpigmentation, and melanoma. Among the scaffold classes investigated for TYR inhibition, 1,2,4-triazole derivatives have attracted increasing interest. In this study, we evaluated a structurally diverse series of triazole derivatives using an integrated computational workflow that included absorption, distribution, metabolism, excretion and toxicity (ADMET) profiling, molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations based on Linear Interaction Energy (LIE) and Free Energy Perturbation (FEP). Using\n                    <jats:italic>Bacillus megaterium<\/jats:italic>\n                    TYR as the model enzyme, the triazole derivatives generally produced more favorable docking scores than kojic acid and established recurring interactions with hydrophobic residues such as Met215, Val217, Ala221, and Phe227, as well as hydrogen-bonding contacts with Gly216. The free energy calculations reproduced the experimental binding affinities with high accuracy (FEP: R\u00b2 = 0.91, MAE\u2009=\u20090.20\u00a0kcal\/mol; LIE: R\u00b2 = 0.93, MAE\u2009=\u20090.54\u00a0kcal\/mol). Residue-level energy analysis indicated that interactions involving Arg209, Gly216 and Val218 play a major role in ligand binding across the series, with aromatic and halogenated substituents favoring stronger van der Waals contacts in this region. Overall, these results provide a consistent structural and energetic framework for understanding triazole-based TYR inhibition and may support the rational design of improved inhibitors for cosmetic and therapeutic applications.\n                  <\/jats:p>","DOI":"10.1007\/s11030-026-11601-7","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T13:47:53Z","timestamp":1780062473000},"page":"8461-8478","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Rational design of triazole tyrosinase inhibitors via integrated free energy calculations"],"prefix":"10.1007","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-2299-6688","authenticated-orcid":false,"given":"Nath\u00e1lia Luiza Oliveira","family":"Costa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6576-4229","authenticated-orcid":false,"given":"Cl\u00e1udio Nahum","family":"Alves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8580-2736","authenticated-orcid":false,"given":"Lucas Sousa","family":"Martins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2310-5107","authenticated-orcid":false,"given":"Jos\u00e9 Rog\u00e9rio A.","family":"Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,29]]},"reference":[{"key":"11601_CR1","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1007\/s40828-024-00195-y","volume":"10","author":"M Pretzler","year":"2024","unstructured":"Pretzler M, Rompel A (2024) Tyrosinases: a family of copper-containing metalloenzymes. ChemTexts 10:12. https:\/\/doi.org\/10.1007\/s40828-024-00195-y","journal-title":"ChemTexts"},{"key":"11601_CR2","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1152\/physrev.1928.8.2.245","volume":"8","author":"HS Raper","year":"1928","unstructured":"Raper HS (1928) The aerobic oxidases. Physiol Rev 8:245\u2013282. https:\/\/doi.org\/10.1152\/physrev.1928.8.2.245","journal-title":"Physiol Rev"},{"key":"11601_CR3","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/s0021-9258(18)35614-x","volume":"172","author":"HS Mason","year":"1948","unstructured":"Mason HS (1948) The chemistry of melanin. J Biol Chem 172:83\u201399. https:\/\/doi.org\/10.1016\/s0021-9258(18)35614-x","journal-title":"J Biol Chem"},{"key":"11601_CR4","doi-asserted-by":"publisher","first-page":"9812","DOI":"10.1002\/anie.201704616","volume":"56","author":"X Lai","year":"2017","unstructured":"Lai X, Wichers HJ, Soler-Lopez M, Dijkstra BW (2017) Structure of human tyrosinase related protein 1 reveals a binuclear zinc active site important for melanogenesis. Angew Chem Int Ed Engl 56:9812\u20139815. https:\/\/doi.org\/10.1002\/anie.201704616","journal-title":"Angew Chem Int Ed Engl"},{"key":"11601_CR5","doi-asserted-by":"publisher","first-page":"1707","DOI":"10.1007\/s00018-005-5054-y","volume":"62","author":"Y-J Kim","year":"2005","unstructured":"Kim Y-J, Uyama H (2005) Tyrosinase inhibitors from natural and synthetic sources: structure, inhibition mechanism and perspective for the future. Cell Mol Life Sci 62:1707\u20131723. https:\/\/doi.org\/10.1007\/s00018-005-5054-y","journal-title":"Cell Mol Life Sci"},{"key":"11601_CR6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/0167-4838(94)00204-t","volume":"1247","author":"A S\u00e1nchez-Ferrer","year":"1995","unstructured":"S\u00e1nchez-Ferrer A, Rodr\u00edguez-L\u00f3pez JN, Garc\u00eda-C\u00e1novas F, Garc\u00eda-Carmona F (1995) Tyrosinase: a comprehensive review of its mechanism. Biochim Biophys Acta 1247:1\u201311. https:\/\/doi.org\/10.1016\/0167-4838(94)00204-t","journal-title":"Biochim Biophys Acta"},{"key":"11601_CR7","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1080\/14756366.2016.1256882","volume":"32","author":"T Pillaiyar","year":"2017","unstructured":"Pillaiyar T, Manickam M, Namasivayam V (2017) Skin whitening agents: medicinal chemistry perspective of tyrosinase inhibitors. J Enzyme Inhib Med Chem 32:403\u2013425. https:\/\/doi.org\/10.1080\/14756366.2016.1256882","journal-title":"J Enzyme Inhib Med Chem"},{"key":"11601_CR8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/978-3-319-53805-1_81","volume-title":"Atlas of Dermatology, Dermatopathology and Venereology","author":"J Ruiz Beguerie","year":"2021","unstructured":"Ruiz Beguerie J, de Diego C (2021) Freckles, Lentigos, Melanocytic Nevi, and Melanoma. Atlas of Dermatology, Dermatopathology and Venereology. Springer International Publishing, Cham, pp 1\u201331. https:\/\/doi.org\/10.1007\/978-3-319-53805-1_81"},{"key":"11601_CR9","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1016\/bs.enz.2024.05.005","volume":"56","author":"L Pisano","year":"2024","unstructured":"Pisano L, Turco M, Supuran CT (2024) Biomedical applications of tyrosinases and tyrosinase inhibitors. Enzymes 56:261\u2013280. https:\/\/doi.org\/10.1016\/bs.enz.2024.05.005","journal-title":"Enzymes"},{"key":"11601_CR10","doi-asserted-by":"publisher","first-page":"5762","DOI":"10.3390\/molecules28155762","volume":"28","author":"MA Baber","year":"2023","unstructured":"Baber MA, Crist CM, Devolve NL, Patrone JD (2023) Tyrosinase inhibitors: A perspective. Molecules 28:5762. https:\/\/doi.org\/10.3390\/molecules28155762","journal-title":"Molecules"},{"key":"11601_CR11","doi-asserted-by":"publisher","first-page":"4839","DOI":"10.3390\/molecules28124839","volume":"28","author":"AM Thawabteh","year":"2023","unstructured":"Thawabteh AM, Jibreen A, Karaman D et al (2023) Skin pigmentation types, causes and treatment-A review. Molecules 28:4839. https:\/\/doi.org\/10.3390\/molecules28124839","journal-title":"Molecules"},{"key":"11601_CR12","doi-asserted-by":"publisher","first-page":"2440","DOI":"10.3390\/ijms10062440","volume":"10","author":"T-S Chang","year":"2009","unstructured":"Chang T-S (2009) An updated review of tyrosinase inhibitors. Int J Mol Sci 10:2440\u20132475. https:\/\/doi.org\/10.3390\/ijms10062440","journal-title":"Int J Mol Sci"},{"key":"11601_CR13","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1016\/j.biopha.2018.12.006","volume":"110","author":"M Saeedi","year":"2019","unstructured":"Saeedi M, Eslamifar M, Khezri K (2019) Kojic acid applications in cosmetic and pharmaceutical preparations. Biomed Pharmacother 110:582\u2013593. https:\/\/doi.org\/10.1016\/j.biopha.2018.12.006","journal-title":"Biomed Pharmacother"},{"key":"11601_CR14","doi-asserted-by":"publisher","first-page":"244S","DOI":"10.1177\/1091581810385956","volume":"29","author":"CL Burnett","year":"2010","unstructured":"Burnett CL, Bergfeld WF, Belsito DV et al (2010) Final report of the safety assessment of Kojic acid as used in cosmetics. Int J Toxicol 29:244S\u20132473. https:\/\/doi.org\/10.1177\/1091581810385956","journal-title":"Int J Toxicol"},{"key":"11601_CR15","doi-asserted-by":"publisher","first-page":"1842","DOI":"10.1007\/s00044-022-02954-3","volume":"31","author":"S Emami","year":"2022","unstructured":"Emami S, Ahmadi R, Ahadi H, Ashooriha M (2022) Diverse therapeutic potential of 3-hydroxy-4-pyranones and related compounds as kojic acid analogs. Med Chem Res 31:1842\u20131861. https:\/\/doi.org\/10.1007\/s00044-022-02954-3","journal-title":"Med Chem Res"},{"key":"11601_CR16","doi-asserted-by":"publisher","DOI":"10.1007\/s11030-026-11487-5","author":"Y Wen","year":"2026","unstructured":"Wen Y, Yu Q, Yang F et al (2026) Synthesis and biological evaluation of novel Kojic acid-cinnamic acid hybrids as tyrosinase inhibitors. Mol Divers. https:\/\/doi.org\/10.1007\/s11030-026-11487-5","journal-title":"Mol Divers"},{"key":"11601_CR17","doi-asserted-by":"publisher","first-page":"4540","DOI":"10.1039\/d5md00403a","volume":"16","author":"M Ward","year":"2025","unstructured":"Ward M, O\u2019Boyle NM (2025) Analysis of the structural diversity of heterocycles amongst European medicines agency approved pharmaceuticals (2014\u20132023). RSC Med Chem 16:4540\u20134570. https:\/\/doi.org\/10.1039\/d5md00403a","journal-title":"RSC Med Chem"},{"key":"11601_CR18","doi-asserted-by":"publisher","first-page":"2958","DOI":"10.1021\/cr300176g","volume":"113","author":"B Eftekhari-Sis","year":"2013","unstructured":"Eftekhari-Sis B, Zirak M, Akbari A (2013) Arylglyoxals in synthesis of heterocyclic compounds. Chem Rev 113:2958\u20133043. https:\/\/doi.org\/10.1021\/cr300176g","journal-title":"Chem Rev"},{"key":"11601_CR19","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.3390\/ph15081026","volume":"15","author":"A \u0160ermuk\u0161nyt\u0117","year":"2022","unstructured":"\u0160ermuk\u0161nyt\u0117 A, Kantminien\u0117 K, Jonu\u0161kien\u0117 I et al (2022) The effect of 1,2,4-triazole-3-thiol derivatives bearing hydrazone moiety on cancer cell migration and growth of melanoma, breast, and pancreatic cancer spheroids. Pharmaceuticals (Basel) 15:1026. https:\/\/doi.org\/10.3390\/ph15081026","journal-title":"Pharmaceuticals (Basel)"},{"key":"11601_CR20","doi-asserted-by":"publisher","first-page":"140722","DOI":"10.1016\/j.molstruc.2024.140722","volume":"1323","author":"H Tahtaci","year":"2025","unstructured":"Tahtaci H, Ozcan I, Mirghani AH et al (2025) 1,2,4-Triazole-derived oxime ether derivatives: Synthesis, characterization, in vitro tyrosinase inhibition properties and in silico studies. J Mol Struct 1323:140722. https:\/\/doi.org\/10.1016\/j.molstruc.2024.140722","journal-title":"J Mol Struct"},{"key":"11601_CR21","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.compbiolchem.2018.03.007","volume":"74","author":"B De","year":"2018","unstructured":"De B, Adhikari I, Nandy A et al (2018) In silico modelling of azole derivatives with tyrosinase inhibition ability: Application of the models for activity prediction of new compounds. Comput Biol Chem 74:105\u2013114. https:\/\/doi.org\/10.1016\/j.compbiolchem.2018.03.007","journal-title":"Comput Biol Chem"},{"key":"11601_CR22","doi-asserted-by":"publisher","first-page":"e2100058","DOI":"10.1002\/ardp.202100058","volume":"354","author":"E Gultekin","year":"2021","unstructured":"Gultekin E, Bekircan O, Kolcuo\u011flu Y, Akdemir A (2021) Synthesis of new 1,2,4-triazole-(thio)semicarbazide hybrid molecules: Their tyrosinase inhibitor activities and molecular docking analysis. Arch Pharm (Weinheim) 354:e2100058. https:\/\/doi.org\/10.1002\/ardp.202100058","journal-title":"Arch Pharm (Weinheim)"},{"key":"11601_CR23","doi-asserted-by":"publisher","first-page":"104979","DOI":"10.1016\/j.bioorg.2021.104979","volume":"114","author":"H Hosseinpoor","year":"2021","unstructured":"Hosseinpoor H, Moghadam Farid S, Iraji A et al (2021) Anti-melanogenesis and anti-tyrosinase properties of aryl-substituted acetamides of phenoxy methyl triazole conjugated with thiosemicarbazide: Design, synthesis and biological evaluations. Bioorg Chem 114:104979. https:\/\/doi.org\/10.1016\/j.bioorg.2021.104979","journal-title":"Bioorg Chem"},{"key":"11601_CR24","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1016\/j.bioorg.2019.01.036","volume":"86","author":"ARS Butt","year":"2019","unstructured":"Butt ARS, Abbasi MA, Aziz-Ur-Rehman et al (2019) Synthesis and structure-activity relationship of tyrosinase inhibiting novel bi-heterocyclic acetamides: Mechanistic insights through enzyme inhibition, kinetics and computational studies. Bioorg Chem 86:459\u2013472. https:\/\/doi.org\/10.1016\/j.bioorg.2019.01.036","journal-title":"Bioorg Chem"},{"key":"11601_CR25","doi-asserted-by":"publisher","first-page":"114525","DOI":"10.1016\/j.ejmech.2022.114525","volume":"239","author":"U Ghani","year":"2022","unstructured":"Ghani U (2022) Azole inhibitors of mushroom and human tyrosinases: Current advances and prospects of drug development for melanogenic dermatological disorders. Eur J Med Chem 239:114525. https:\/\/doi.org\/10.1016\/j.ejmech.2022.114525","journal-title":"Eur J Med Chem"},{"key":"11601_CR26","doi-asserted-by":"publisher","first-page":"2089","DOI":"10.1007\/s11030-020-10102-5","volume":"25","author":"BD Vanjare","year":"2021","unstructured":"Vanjare BD, Mahajan PG, Dige NC et al (2021) Novel 1,2,4-triazole analogues as mushroom tyrosinase inhibitors: synthesis, kinetic mechanism, cytotoxicity and computational studies. Mol Divers 25:2089\u20132106. https:\/\/doi.org\/10.1007\/s11030-020-10102-5","journal-title":"Mol Divers"},{"key":"11601_CR27","doi-asserted-by":"publisher","first-page":"140722","DOI":"10.1016\/j.foodchem.2024.140722","volume":"460","author":"J Zhang","year":"2024","unstructured":"Zhang J, Yang W, He M et al (2024) Development of novel pyrazole-1,2,4-triazole derivatives as tyrosinase inhibitors: Design, preparation, mechanism of action and anti-browning application. Food Chem 460:140722. https:\/\/doi.org\/10.1016\/j.foodchem.2024.140722","journal-title":"Food Chem"},{"key":"11601_CR28","doi-asserted-by":"publisher","first-page":"113705","DOI":"10.1016\/j.ejmech.2021.113705","volume":"224","author":"VT Sabe","year":"2021","unstructured":"Sabe VT, Ntombela T, Jhamba LA et al (2021) Current trends in computer aided drug design and a highlight of drugs discovered via computational techniques: A review. Eur J Med Chem 224:113705. https:\/\/doi.org\/10.1016\/j.ejmech.2021.113705","journal-title":"Eur J Med Chem"},{"key":"11601_CR29","doi-asserted-by":"publisher","first-page":"4783","DOI":"10.3390\/ijms21134783","volume":"21","author":"LS Martins","year":"2020","unstructured":"Martins LS, Lameira J, Kruger HG et al (2020) Evaluating the performance of a non-bonded Cu2\u2009+\u2009model including Jahn-Teller effect into the binding of tyrosinase inhibitors. Int J Mol Sci 21:4783. https:\/\/doi.org\/10.3390\/ijms21134783","journal-title":"Int J Mol Sci"},{"key":"11601_CR30","doi-asserted-by":"publisher","first-page":"8141","DOI":"10.3390\/molecules27238141","volume":"27","author":"LS Martins","year":"2022","unstructured":"Martins LS, Gon\u00e7alves RWA, Moraes JJS et al (2022) Computational analysis of triazole-based kojic acid analogs as Tyrosinase inhibitors by molecular dynamics and free energy calculations. Molecules 27:8141. https:\/\/doi.org\/10.3390\/molecules27238141","journal-title":"Molecules"},{"key":"11601_CR31","doi-asserted-by":"publisher","first-page":"115085","DOI":"10.1016\/j.comptc.2025.115085","volume":"1244","author":"LS Martins","year":"2025","unstructured":"Martins LS, Bentes BA, Naicker T et al (2025) Unravelling the mechanism of tyrosinase inhibition by arylpiperidine and arylpiperazine derivatives: A computational approach. Comput Theor Chem 1244:115085. https:\/\/doi.org\/10.1016\/j.comptc.2025.115085","journal-title":"Comput Theor Chem"},{"key":"11601_CR32","doi-asserted-by":"publisher","first-page":"804","DOI":"10.1111\/cbdd.13001","volume":"90","author":"EM Brasil","year":"2017","unstructured":"Brasil EM, Canavieira LM, Cardoso \u00c9TC et al (2017) Inhibition of tyrosinase by 4H-chromene analogs: Synthesis, kinetic studies, and computational analysis. Chem Biol Drug Des 90:804\u2013810. https:\/\/doi.org\/10.1111\/cbdd.13001","journal-title":"Chem Biol Drug Des"},{"key":"11601_CR33","doi-asserted-by":"publisher","first-page":"9591","DOI":"10.3390\/molecules19079591","volume":"19","author":"CR Lima","year":"2014","unstructured":"Lima CR, Silva JRA, de T\u00e1ssia Carvalho Cardoso E et al (2014) Combined kinetic studies and computational analysis on kojic acid analogous as tyrosinase inhibitors. Molecules 19:9591\u20139605. https:\/\/doi.org\/10.3390\/molecules19079591","journal-title":"Molecules"},{"key":"11601_CR34","doi-asserted-by":"publisher","first-page":"42717","DOI":"10.1038\/srep42717","volume":"7","author":"A Daina","year":"2017","unstructured":"Daina A, Michielin O, Zoete V (2017) SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 7:42717. https:\/\/doi.org\/10.1038\/srep42717","journal-title":"Sci Rep"},{"key":"11601_CR35","doi-asserted-by":"publisher","first-page":"34993","DOI":"10.1038\/srep34993","volume":"6","author":"B Deri","year":"2016","unstructured":"Deri B, Kanteev M, Goldfeder M et al (2016) The unravelling of the complex pattern of tyrosinase inhibition. Sci Rep 6:34993. https:\/\/doi.org\/10.1038\/srep34993","journal-title":"Sci Rep"},{"key":"11601_CR36","doi-asserted-by":"publisher","first-page":"5477","DOI":"10.1021\/bi200395t","volume":"50","author":"WT Ismaya","year":"2011","unstructured":"Ismaya WT, Rozeboom HJ, Weijn A et al (2011) Crystal structure of Agaricus bisporus mushroom tyrosinase: identity of the tetramer subunits and interaction with tropolone. Biochemistry 50:5477\u20135486. https:\/\/doi.org\/10.1021\/bi200395t","journal-title":"Biochemistry"},{"key":"11601_CR37","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1021\/acsmedchemlett.6b00369","volume":"8","author":"R Haudecoeur","year":"2017","unstructured":"Haudecoeur R, Carotti M, Gouron A et al (2017) 2-hydroxypyridine-N-oxide-embedded aurones as potent human tyrosinase inhibitors. ACS Med Chem Lett 8:55\u201360. https:\/\/doi.org\/10.1021\/acsmedchemlett.6b00369","journal-title":"ACS Med Chem Lett"},{"key":"11601_CR38","doi-asserted-by":"publisher","first-page":"3315","DOI":"10.1021\/jm051197e","volume":"49","author":"R Thomsen","year":"2006","unstructured":"Thomsen R, Christensen MH (2006) MolDock: a new technique for high-accuracy molecular docking. J Med Chem 49:3315\u20133321. https:\/\/doi.org\/10.1021\/jm051197e","journal-title":"J Med Chem"},{"key":"11601_CR39","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1088\/0959-5309\/43\/5\/301","volume":"43","author":"JE Lennard-Jones","year":"1931","unstructured":"Lennard-Jones JE (1931) Cohesion. Proc Phys Soc 43:461\u2013482. https:\/\/doi.org\/10.1088\/0959-5309\/43\/5\/301","journal-title":"Proc Phys Soc"},{"key":"11601_CR40","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1021\/acsmedchemlett.2c00541","volume":"14","author":"I Muegge","year":"2023","unstructured":"Muegge I, Hu Y (2023) Recent advances in alchemical binding free energy calculations for drug discovery. ACS Med Chem Lett 14:244\u2013250. https:\/\/doi.org\/10.1021\/acsmedchemlett.2c00541","journal-title":"ACS Med Chem Lett"},{"key":"11601_CR41","doi-asserted-by":"publisher","first-page":"1100","DOI":"10.2174\/138945008786949360","volume":"9","author":"HLN de Amorim","year":"2008","unstructured":"de Amorim HLN, Caceres RA, Netz PA (2008) Linear interaction energy (LIE) method in lead discovery and optimization. Curr Drug Targets 9:1100\u20131105. https:\/\/doi.org\/10.2174\/138945008786949360","journal-title":"Curr Drug Targets"},{"key":"11601_CR42","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1016\/j.softx.2017.12.001","volume":"7","author":"P Bauer","year":"2018","unstructured":"Bauer P, Barrozo A, Purg M et al (2018) Q6: A comprehensive toolkit for empirical valence bond and related free energy calculations. SoftwareX 7:388\u2013395. https:\/\/doi.org\/10.1016\/j.softx.2017.12.001","journal-title":"SoftwareX"},{"key":"11601_CR43","doi-asserted-by":"publisher","first-page":"W665","DOI":"10.1093\/nar\/gkh381","volume":"32","author":"TJ Dolinsky","year":"2004","unstructured":"Dolinsky TJ, Nielsen JE, McCammon JA, Baker NA (2004) PDB2PQR: an automated pipeline for the setup of Poisson-Boltzmann electrostatics calculations. Nucleic Acids Res 32:W665\u2013W667. https:\/\/doi.org\/10.1093\/nar\/gkh381","journal-title":"Nucleic Acids Res"},{"key":"11601_CR44","doi-asserted-by":"publisher","first-page":"704","DOI":"10.1002\/prot.20660","volume":"61","author":"H Li","year":"2005","unstructured":"Li H, Robertson AD, Jensen JH (2005) Very fast empirical prediction and rationalization of protein pKa values. Proteins 61:704\u2013721. https:\/\/doi.org\/10.1002\/prot.20660","journal-title":"Proteins"},{"key":"11601_CR45","doi-asserted-by":"publisher","first-page":"3499","DOI":"10.1021\/acs.jctc.5b00356","volume":"11","author":"MJ Robertson","year":"2015","unstructured":"Robertson MJ, Tirado-Rives J, Jorgensen WL (2015) Improved peptide and protein torsional energetics with the OPLSAA force field. J Chem Theory Comput 11:3499\u20133509. https:\/\/doi.org\/10.1021\/acs.jctc.5b00356","journal-title":"J Chem Theory Comput"},{"key":"11601_CR46","doi-asserted-by":"publisher","first-page":"2657","DOI":"10.1021\/acs.jpclett.5b01122","volume":"6","author":"Q Liao","year":"2015","unstructured":"Liao Q, Kamerlin SCL, Strodel B (2015) Development and application of a nonbonded Cu(2+) model that includes the Jahn-Teller effect. J Phys Chem Lett 6:2657\u20132662. https:\/\/doi.org\/10.1021\/acs.jpclett.5b01122","journal-title":"J Phys Chem Lett"},{"key":"11601_CR47","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1002\/jcc.540110405","volume":"11","author":"F Mohamadi","year":"1990","unstructured":"Mohamadi F, Richards NGJ, Guida WC et al (1990) Macromodel\u2014an integrated software system for modeling organic and bioorganic molecules using molecular mechanics. J Comput Chem 11:440\u2013467. https:\/\/doi.org\/10.1002\/jcc.540110405","journal-title":"J Comput Chem"},{"key":"11601_CR48","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1063\/1.445869","volume":"79","author":"WL Jorgensen","year":"1983","unstructured":"Jorgensen WL, Chandrasekhar J, Madura JD et al (1983) Comparison of simple potential functions for simulating liquid water. J Chem Phys 79:926\u2013935. https:\/\/doi.org\/10.1063\/1.445869","journal-title":"J Chem Phys"},{"key":"11601_CR49","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1016\/0021-9991(77)90098-5","volume":"23","author":"J-P Ryckaert","year":"1977","unstructured":"Ryckaert J-P, Ciccotti G, Berendsen HJC (1977) Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J Comput Phys 23:327\u2013341. https:\/\/doi.org\/10.1016\/0021-9991(77)90098-5","journal-title":"J Comput Phys"},{"key":"11601_CR50","doi-asserted-by":"publisher","first-page":"3647","DOI":"10.1063\/1.456845","volume":"91","author":"G King","year":"1989","unstructured":"King G, Warshel A (1989) A surface constrained all-atom solvent model for effective simulations of polar solutions. J Chem Phys 91:3647\u20133661. https:\/\/doi.org\/10.1063\/1.456845","journal-title":"J Chem Phys"},{"key":"11601_CR51","doi-asserted-by":"publisher","first-page":"3100","DOI":"10.1063\/1.462997","volume":"97","author":"FS Lee","year":"1992","unstructured":"Lee FS, Warshel A (1992) A local reaction field method for fast evaluation of long-range electrostatic interactions in molecular simulations. J Chem Phys 97:3100\u20133107. https:\/\/doi.org\/10.1063\/1.462997","journal-title":"J Chem Phys"},{"key":"11601_CR52","doi-asserted-by":"publisher","unstructured":"Bufarwa SM, Belaidi M, Abbass LM, Thbayh DK (2025) Anticancer activity, DFT, molecular docking, ADMET, and molecular dynamics simulations investigations of Schiff base derived from 2,3-diaminophenazine and its metal complexes. Appl Organomet Chem 39. https:\/\/doi.org\/10.1002\/aoc.7953","DOI":"10.1002\/aoc.7953"},{"key":"11601_CR53","doi-asserted-by":"publisher","first-page":"108502","DOI":"10.1016\/j.compbiolchem.2025.108502","volume":"118","author":"M Suliman","year":"2025","unstructured":"Suliman M, Laraib A, Bibi S et al (2025) The exploring AI-generated pyrazalone derivatives as antifungal agents: Bringing together molecular docking and quantum chemical approaches. Comput Biol Chem 118:108502. https:\/\/doi.org\/10.1016\/j.compbiolchem.2025.108502","journal-title":"Comput Biol Chem"},{"key":"11601_CR54","doi-asserted-by":"publisher","unstructured":"Alshahrani MY, Laraib A, Bibi S et al (2026) Design and mechanistic analysis of novel antiallergic agents using integrative computational approaches comprising molecular docking, DFT, simulation dynamics, and retrosynthesis studies. Polycycl Aromat Compd 1\u201324. https:\/\/doi.org\/10.1080\/10406638.2026.2621954","DOI":"10.1080\/10406638.2026.2621954"},{"key":"11601_CR55","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.5c02932","author":"D Alencar Araripe","year":"2026","unstructured":"Alencar Araripe D, D\u00edaz-Holgu\u00edn A, Poso A et al (2026) Doing more with less: Accurate and scalable ligand free energy calculations by focusing on the binding site. J Chem Inf Model. https:\/\/doi.org\/10.1021\/acs.jcim.5c02932","journal-title":"J Chem Inf Model"},{"key":"11601_CR56","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1093\/protein\/7.3.385","volume":"7","author":"J \u00c5qvist","year":"1994","unstructured":"\u00c5qvist J, Medina C, Samuelsson J-E (1994) A new method for predicting binding affinity in computer-aided drug design. Protein Eng Des Sel 7:385\u2013391. https:\/\/doi.org\/10.1093\/protein\/7.3.385","journal-title":"Protein Eng Des Sel"},{"key":"11601_CR57","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1023\/a:1007930623000","volume":"12","author":"T Hansson","year":"1998","unstructured":"Hansson T, Marelius J, Aqvist J (1998) Ligand binding affinity prediction by linear interaction energy methods. J Comput Aided Mol Des 12:27\u201335. https:\/\/doi.org\/10.1023\/a:1007930623000","journal-title":"J Comput Aided Mol Des"},{"key":"11601_CR58","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1021\/acs.jcim.5b00057","volume":"55","author":"S Liu","year":"2015","unstructured":"Liu S, Wang L, Mobley DL (2015) Is ring breaking feasible in relative binding free energy calculations? J Chem Inf Model 55:727\u2013735. https:\/\/doi.org\/10.1021\/acs.jcim.5b00057","journal-title":"J Chem Inf Model"},{"key":"11601_CR59","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1021\/acs.jctc.6b00991","volume":"13","author":"L Wang","year":"2017","unstructured":"Wang L, Deng Y, Wu Y et al (2017) Accurate modeling of scaffold hopping transformations in drug discovery. J Chem Theory Comput 13:42\u201354. https:\/\/doi.org\/10.1021\/acs.jctc.6b00991","journal-title":"J Chem Theory Comput"},{"key":"11601_CR60","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/s13321-019-0348-5","volume":"11","author":"W Jespers","year":"2019","unstructured":"Jespers W, Esguerra M, \u00c5qvist J, Guti\u00e9rrez-de-Ter\u00e1n H (2019) QligFEP: an automated workflow for small molecule free energy calculations in Q. J Cheminform 11:26. https:\/\/doi.org\/10.1186\/s13321-019-0348-5","journal-title":"J Cheminform"},{"key":"11601_CR61","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1016\/0009-2614(94)00397-1","volume":"222","author":"TC Beutler","year":"1994","unstructured":"Beutler TC, Mark AE, van Schaik RC et al (1994) Avoiding singularities and numerical instabilities in free energy calculations based on molecular simulations. Chem Phys Lett 222:529\u2013539. https:\/\/doi.org\/10.1016\/0009-2614(94)00397-1","journal-title":"Chem Phys Lett"},{"key":"11601_CR62","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/s0169-409x(96)00423-1","volume":"23","author":"CA Lipinski","year":"1997","unstructured":"Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 23:3\u201325. https:\/\/doi.org\/10.1016\/s0169-409x(96)00423-1","journal-title":"Adv Drug Deliv Rev"},{"key":"11601_CR63","doi-asserted-by":"publisher","unstructured":"Laraib A, UrRehman S, Jamil S et al (2025) Aloin as a potential anti-Breast Cancer agent: Insights from molecular docking and density functional theory (DFT) analysis. https:\/\/doi.org\/10.1002\/slct.202406211. ChemistrySelect 10:","DOI":"10.1002\/slct.202406211"},{"key":"11601_CR64","doi-asserted-by":"publisher","first-page":"1871","DOI":"10.1007\/s11696-025-04495-6","volume":"80","author":"A Maqbool","year":"2026","unstructured":"Maqbool A, Laraib A, Ali N et al (2026) Designing structural derivatives of EGCG from Chinese tea for improved antioxidant activity: DFT study. Chem Pap 80:1871\u20131879. https:\/\/doi.org\/10.1007\/s11696-025-04495-6","journal-title":"Chem Pap"},{"key":"11601_CR65","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1007\/s12539-019-00327-w","volume":"11","author":"J Li","year":"2019","unstructured":"Li J, Fu A, Zhang L (2019) An overview of scoring functions used for protein-ligand interactions in molecular docking. Interdiscip Sci 11:320\u2013328. https:\/\/doi.org\/10.1007\/s12539-019-00327-w","journal-title":"Interdiscip Sci"},{"key":"11601_CR66","doi-asserted-by":"publisher","first-page":"1084","DOI":"10.1038\/4193","volume":"5","author":"T Klabunde","year":"1998","unstructured":"Klabunde T, Eicken C, Sacchettini JC, Krebs B (1998) Crystal structure of a plant catechol oxidase containing a dicopper center. Nat Struct Biol 5:1084\u20131090. https:\/\/doi.org\/10.1038\/4193","journal-title":"Nat Struct Biol"},{"key":"11601_CR67","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1186\/1472-6750-13-18","volume":"13","author":"Q Ren","year":"2013","unstructured":"Ren Q, Henes B, Fairhead M, Th\u00f6ny-Meyer L (2013) High level production of tyrosinase in recombinant Escherichia coli. BMC Biotechnol 13:18. https:\/\/doi.org\/10.1186\/1472-6750-13-18","journal-title":"BMC Biotechnol"},{"key":"11601_CR68","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.ijbiomac.2021.02.042","volume":"176","author":"F Wang","year":"2021","unstructured":"Wang F, Xu Z, Wang C et al (2021) Biochemical characterization of a tyrosinase from Bacillus aryabhattai and its application. Int J Biol Macromol 176:37\u201346. https:\/\/doi.org\/10.1016\/j.ijbiomac.2021.02.042","journal-title":"Int J Biol Macromol"},{"key":"11601_CR69","doi-asserted-by":"publisher","first-page":"914944","DOI":"10.3389\/fchem.2022.914944","volume":"10","author":"Y-G Hu","year":"2022","unstructured":"Hu Y-G, Gao Z-P, Zheng Y-Y et al (2022) Synthesis and biological activity evaluation of 2-cyanopyrrole derivatives as potential tyrosinase inhibitors. Front Chem 10:914944. https:\/\/doi.org\/10.3389\/fchem.2022.914944","journal-title":"Front Chem"},{"key":"11601_CR70","doi-asserted-by":"publisher","first-page":"7470","DOI":"10.3390\/molecules28227470","volume":"28","author":"L Lu","year":"2023","unstructured":"Lu L, Hu C, Min X et al (2023) In vitro and in vivo biological evaluation of indole-thiazolidine-2,4-dione derivatives as tyrosinase inhibitors. Molecules 28:7470. https:\/\/doi.org\/10.3390\/molecules28227470","journal-title":"Molecules"},{"key":"11601_CR71","doi-asserted-by":"publisher","first-page":"122644","DOI":"10.1016\/j.saa.2023.122644","volume":"296","author":"Q Chen","year":"2023","unstructured":"Chen Q, Shang C, Han M et al (2023) Inhibitory mechanism of scutellarein on tyrosinase by kinetics, spectroscopy and molecular simulation. Spectrochim Acta Mol Biomol Spectrosc 296:122644. https:\/\/doi.org\/10.1016\/j.saa.2023.122644","journal-title":"Spectrochim Acta Mol Biomol Spectrosc"},{"key":"11601_CR72","doi-asserted-by":"publisher","first-page":"359","DOI":"10.3390\/md22080359","volume":"22","author":"F Li","year":"2024","unstructured":"Li F, Lin H, Qin X et al (2024) In silico identification and molecular mechanism of novel tyrosinase inhibitory peptides derived from nacre of Pinctada martensii. Mar Drugs 22:359. https:\/\/doi.org\/10.3390\/md22080359","journal-title":"Mar Drugs"},{"key":"11601_CR73","doi-asserted-by":"publisher","first-page":"13509","DOI":"10.3390\/ijms252413509","volume":"25","author":"M Dymek","year":"2024","unstructured":"Dymek M, Warszycki D, Podlewska S, Sikora E (2024) Novel tripeptides as tyrosinase inhibitors: In silico and in vitro approaches. Int J Mol Sci 25:13509. https:\/\/doi.org\/10.3390\/ijms252413509","journal-title":"Int J Mol Sci"},{"key":"11601_CR74","doi-asserted-by":"publisher","first-page":"625274","DOI":"10.3389\/fmolb.2021.625274","volume":"8","author":"SR Vanga","year":"2021","unstructured":"Vanga SR, \u00c5qvist J, Hallberg A, Guti\u00e9rrez-de-Ter\u00e1n H (2021) Structural basis of inhibition of human insulin-regulated aminopeptidase (IRAP) by benzopyran-based inhibitors. Front Mol Biosci 8:625274. https:\/\/doi.org\/10.3389\/fmolb.2021.625274","journal-title":"Front Mol Biosci"},{"key":"11601_CR75","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1006\/jmbi.1994.1430","volume":"240","author":"AE Mark","year":"1994","unstructured":"Mark AE, van Gunsteren WF (1994) Decomposition of the free energy of a system in terms of specific interactions. Implications for theoretical and experimental studies. J Mol Biol 240:167\u2013176. https:\/\/doi.org\/10.1006\/jmbi.1994.1430","journal-title":"J Mol Biol"},{"key":"11601_CR76","doi-asserted-by":"publisher","first-page":"2648","DOI":"10.1021\/jm7012198","volume":"51","author":"J Carlsson","year":"2008","unstructured":"Carlsson J, Boukharta L, Aqvist J (2008) Combining docking, molecular dynamics and the linear interaction energy method to predict binding modes and affinities for non-nucleoside inhibitors to HIV-1 reverse transcriptase. J Med Chem 51:2648\u20132656. https:\/\/doi.org\/10.1021\/jm7012198","journal-title":"J Med Chem"},{"key":"11601_CR77","doi-asserted-by":"publisher","first-page":"1360","DOI":"10.1002\/pro.2734","volume":"24","author":"M Kanteev","year":"2015","unstructured":"Kanteev M, Goldfeder M, Fishman A (2015) Structure-function correlations in tyrosinases. Protein Sci 24:1360\u20131369. https:\/\/doi.org\/10.1002\/pro.2734","journal-title":"Protein Sci"},{"key":"11601_CR78","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1016\/j.enzmictec.2010.08.008","volume":"47","author":"V Shuster Ben-Yosef","year":"2010","unstructured":"Shuster Ben-Yosef V, Sendovski M, Fishman A (2010) Directed evolution of tyrosinase for enhanced monophenolase\/diphenolase activity ratio. Enzyme Microb Technol 47:372\u2013376. https:\/\/doi.org\/10.1016\/j.enzmictec.2010.08.008","journal-title":"Enzyme Microb Technol"},{"key":"11601_CR79","doi-asserted-by":"publisher","first-page":"1161","DOI":"10.1002\/cbic.202000647","volume":"22","author":"I Kampatsikas","year":"2021","unstructured":"Kampatsikas I, Rompel A (2021) Similar but still different: Which amino acid residues are responsible for varying activities in type-III copper enzymes? ChemBioChem 22:1161\u20131175. https:\/\/doi.org\/10.1002\/cbic.202000647","journal-title":"ChemBioChem"}],"container-title":["Molecular Diversity"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11030-026-11601-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11030-026-11601-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11030-026-11601-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T13:47:17Z","timestamp":1791121637000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11030-026-11601-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,29]]},"references-count":79,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["11601"],"URL":"https:\/\/doi.org\/10.1007\/s11030-026-11601-7","relation":{},"ISSN":["1573-501X"],"issn-type":[{"value":"1573-501X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,29]]},"assertion":[{"value":"4 April 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 May 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 May 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interest","group":{"name":"EthicsHeading","label":"Declarations"}}]}}