{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T04:47:29Z","timestamp":1785905249000,"version":"3.56.0"},"reference-count":105,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>This study investigated the repurposing potential of clomiphene citrate as a topical therapeutic candidate for tegumentary leishmaniasis (TL) and candidiasis. Comparative in silico analyses were performed to evaluate absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties in comparison with meglumine antimoniate and amphotericin B. In addition, molecular docking was conducted to investigate the interaction of clomiphene with Leishmania spp. arginase and the Sap5 protease of Candida albicans. Clomiphene exhibited a favorable physicochemical profile, characterized by high lipophilicity, moderate skin permeability, and predicted oral bioavailability and intestinal absorption superior to those of the reference drugs. Toxicological predictions also indicated a lower systemic toxicity profile compared with conventional therapies. Molecular docking revealed favorable binding energies and interactions with key residues within the active sites of both targets. Experimental assays demonstrated that clomiphene inhibited the early stages of C. albicans biofilm formation and exhibited potent leishmanicidal activity against L. amazonensis promastigotes, with a high selectivity index in macrophages. Together, these findings indicate that clomiphene citrate represents a promising candidate for further investigation as a potential therapeutic agent against tegumentary leishmaniasis and candidiasis.<\/jats:p>","DOI":"10.3390\/biom16081133","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T12:57:56Z","timestamp":1785761876000},"page":"1133","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Repurposing of Clomiphene Citrate and Its Antileishmanial and Antifungal Activities: In Silico and In Vitro Studies"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6051-2540","authenticated-orcid":false,"given":"Leandro Josuel da Costa","family":"Santos","sequence":"first","affiliation":[{"name":"Postgraduate Program in Pharmaceutical Sciences, Federal University of Piau\u00ed, Campus Ministro Petr\u00f4nio Portela, Teresina 64049-550, PI, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c9rika de Ara\u00fajo","family":"Abi-chacra","sequence":"additional","affiliation":[{"name":"Department of Parasitology and Microbiology, Federal University of Piau\u00ed, Campus Ministro Petr\u00f4nio Portela, Teresina 64049-550, PI, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita de C\u00e1ssia Vianna","family":"de Carvalho","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Pharmaceutical Sciences, Federal University of Piau\u00ed, Campus Ministro Petr\u00f4nio Portela, Teresina 64049-550, PI, Brazil"},{"name":"University Center Higher Education Unit Dom Bosco, Curitiba 81010-000, PR, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas Malaquias","family":"Fran\u00e7a","sequence":"additional","affiliation":[{"name":"Undergraduate Course in Pharmacy, Federal University of Piau\u00ed, Campus Ministro Petr\u00f4nio Portela, Teresina 64049-550, PI, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise Andrade","family":"do Nascimento","sequence":"additional","affiliation":[{"name":"Department of Physics, Federal University of Roraima (UFRR), Boa Vista 69310-000, RR, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando A\u00e9cio de Amorim","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Pharmaceutical Sciences, Federal University of Piau\u00ed, Campus Ministro Petr\u00f4nio Portela, Teresina 64049-550, PI, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9957-9697","authenticated-orcid":false,"given":"Gabriel","family":"Zazeri","sequence":"additional","affiliation":[{"name":"Department of Physics, Federal University of Roraima (UFRR), Boa Vista 69310-000, RR, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9 Luis Menezes","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Pharmaceutical Sciences, Federal University of Piau\u00ed, Campus Ministro Petr\u00f4nio Portela, Teresina 64049-550, PI, Brazil"},{"name":"Undergraduate Course in Pharmacy, Federal University of Piau\u00ed, Campus Ministro Petr\u00f4nio Portela, Teresina 64049-550, PI, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e7825","DOI":"10.54751\/revistafoco.v18n2-124","article-title":"Leishmaniasis in the context of public health","volume":"18","author":"Neves","year":"2025","journal-title":"Rev. Foco"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1186\/s12939-025-02691-0","article-title":"Global burden of leishmaniasis, 1990\u20132021: Systematic analysis of the global burden of disease study","volume":"24","author":"Li","year":"2025","journal-title":"Int. J. Equity Health"},{"key":"ref_3","first-page":"e082464","article-title":"Caracteriza\u00e7\u00e3o dos casos de \u00f3bitos por Leishmania no Brasil (2014\u20132023)","volume":"8","author":"Rodrigues","year":"2025","journal-title":"Rev. JRG Estud. Acad."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e13913846679","DOI":"10.33448\/rsd-v13i8.46679","article-title":"Evolu\u00e7\u00e3o cl\u00ednica dos casos de leishmaniose tegumentar no Brasil: Um recorte temporal","volume":"13","author":"Souza","year":"2024","journal-title":"Res. Soc. Dev."},{"key":"ref_5","unstructured":"Brasil, Minist\u00e9rio da Sa\u00fade, Secretaria de Vigil\u00e2ncia em Sa\u00fade, and Departamento de Vigil\u00e2ncia das Doen\u00e7as Transmiss\u00edveis (2017). Manual de Vigil\u00e2ncia da Leishmaniose Tegumentar, Minist\u00e9rio da Sa\u00fade."},{"key":"ref_6","first-page":"1","article-title":"Impacto da vulnerabilidade socioecon\u00f4mica, residencial e de saneamento com a incid\u00eancia de leishmaniose visceral em regi\u00f5es mais pobres","volume":"5","author":"Vieira","year":"2024","journal-title":"An. Jorn. Acad. Eng."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1590\/abd1806-4841.20198388","article-title":"American tegumentary leishmaniasis: Severe side effects of pentavalent antimonial in a patient with chronic renal failure","volume":"94","author":"Marques","year":"2019","journal-title":"An. Bras. Dermatol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Barroso, D.H., Gon\u00e7alves, R.T., Barbosa, J.S., da Motta, J.d.O.C., Freire, G.S.M., Gomes, C.M., and Sampaio, R.N.R. (2022). Meglumine antimoniate was associated with a higher cure rate than liposomal amphotericin B in the treatment of American tegumentary leishmaniasis: A retrospective cohort study from a Leishmania braziliensis-endemic area. Front. Cell. Infect. Microbiol., 12.","DOI":"10.3389\/fcimb.2022.993338"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"taab065","DOI":"10.1093\/jtm\/taab065","article-title":"Efficacy and safety of pentamidine isethionate for tegumentary and visceral human leishmaniasis: A systematic review","volume":"28","author":"Piccica","year":"2021","journal-title":"J. Travel Med."},{"key":"ref_10","unstructured":"OPAS (2022). Diretrizes para o Tratamento das Leishmanioses na Regi\u00e3o das Am\u00e9ricas, Organiza\u00e7\u00e3o Pan-Americana da Sa\u00fade. [2nd ed.]."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Galv\u00e3o, E.L., de Pina Carvalho, J., Machado de Assis, T.S., Freire, M.L., Cota, G., and Nascimento Silva, S. (2024). Quality of life of patients with cutaneous leishmaniasis: A comparative analysis of the EQ-5D-3L and CLIQ questionnaires. PLoS ONE, 19.","DOI":"10.1371\/journal.pone.0298988"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Saidi, N., Blaizot, R., Pr\u00e9vot, G., Aoun, K., Demar, M., Cazenave, P.A., Bouratbine, A., and Pied, S. (2023). Clinical and immunological spectra of human cutaneous leishmaniasis in North Africa and French Guiana. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1134020"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e02272-18","DOI":"10.1128\/mBio.02272-18","article-title":"Repurposing Estrogen Receptor Antagonists for the Treatment of Infectious Disease","volume":"9","author":"Montoya","year":"2018","journal-title":"mBio"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Sifontes-Rodr\u00edguez, S., Escalona-Monta\u00f1o, A.R., Mondrag\u00f3n Flores, R., Mollineda-Diogo, N., Monzote Fidalgo, L., Mondrag\u00f3n-Castel\u00e1n, M.E., Alardin-Guti\u00e9rrez, F., L\u00f3pez-Enzana, L.A., S\u00e1nchez-Almaraz, D.A., and P\u00e9rez-Olvera, O. (2024). Compared Antileishmanial Activity of Clomiphene and Tamoxifen. Biomedicines, 12.","DOI":"10.20944\/preprints202408.0309.v1"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"D1265","DOI":"10.1093\/nar\/gkad976","article-title":"DrugBank 6.0: The DrugBank Knowledgebase for 2024","volume":"52","author":"Knox","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Carter, N.S., Stamper, B.D., Elbarbry, F., Nguyen, V., Lopez, S., Kawasaki, Y., Poormohamadian, R., and Roberts, S.C. (2021). Natural Products That Target the Arginase in Leishmania Parasites Hold Therapeutic Promise. Microorganisms, 9.","DOI":"10.3390\/microorganisms9020267"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.mib.2019.06.003","article-title":"The impact of arginase activity on virulence factors of Leishmania amazonensis","volume":"52","author":"Aoki","year":"2019","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"108453","DOI":"10.1016\/j.compbiolchem.2025.108453","article-title":"Multi-computational screening identifies homovanillic acid as a potential SAP5 inhibitor against Candida albicans biofilms","volume":"118","author":"Kulshrestha","year":"2025","journal-title":"Comput. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1021\/acschembio.2c00879","article-title":"Structural and Biochemical Insights into Post-Translational Arginine-to-Ornithine Peptide Modifications by an Atypical Arginase","volume":"18","author":"Mordhorst","year":"2023","journal-title":"ACS Chem. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Challapa-Mamani, M.R., Tom\u00e1s-Alvarado, E., Espinoza-Baigorria, A., Le\u00f3n-Figueroa, D.A., Sah, R., Rodriguez-Morales, A.J., and Barboza, J.J. (2023). Molecular Docking and Molecular Dynamics Simulations in Related to Leishmania donovani: An Update and Literature Review. Trop. Med. Infect. Dis., 8.","DOI":"10.3390\/tropicalmed8100457"},{"key":"ref_21","unstructured":"Stanzione, F., Giangreco, I., and Cole, J.C. (2021). Use of molecular docking computational tools in drug discovery. Progress in Medicinal Chemistry, Elsevier."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"D1516","DOI":"10.1093\/nar\/gkae1059","article-title":"PubChem 2025 update","volume":"53","author":"Kim","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"D564","DOI":"10.1093\/nar\/gkae1091","article-title":"Updated resources for exploring experimentally-determined PDB structures and Computed Structure Models at the RCSB Protein Data Bank","volume":"53","author":"Burley","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Carvalho Souza, R.A., Oliveira, C.G., de Almeida, G.M., and da Cruz, A.d.S.X. (2023). Previs\u00e3o in silico ADME-Tox de complexos de cobalto (III) derivados de tiossemicarbazonas. Open Science Research XII, Editora Cient\u00edfica Digital.","DOI":"10.37885\/230713656"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1002\/cmdc.201600182","article-title":"A BOILED-Egg To Predict Gastrointestinal Absorption and Brain Penetration of Small Molecules","volume":"11","author":"Daina","year":"2016","journal-title":"ChemMedChem"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"W513","DOI":"10.1093\/nar\/gkae303","article-title":"ProTox 3.0: A webserver for the prediction of toxicity of chemicals","volume":"52","author":"Banerjee","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1080\/15376516.2024.2382815","article-title":"The investigation of the toxicity of organophosphorus flame retardants (OPFRs) by using in silico toxicity prediction platform ProTox-3.0","volume":"35","author":"Banerjee","year":"2025","journal-title":"Toxicol. Mech. Methods"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Lee, H., Kim, J., Kim, J.W., and Lee, Y. (2025). Recent advances in AI-based toxicity prediction for drug discovery. Front. Chem., 13.","DOI":"10.3389\/fchem.2025.1632046"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Boya, B.R., Lee, J.H., Choi, J.M., and Lee, J. (2025). Impact of halogenation on scaffold toxicity assessed using HD-GEM machine learning model. Brief. Bioinform., bbaf347.","DOI":"10.1093\/bib\/bbaf347"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Dulsat, J., L\u00f3pez-Nieto, B., Estrada-Tejedor, R., and Borrell, J.I. (2023). Evaluation of Free Online ADMET Tools for Academic or Small Biotech Environments. Molecules, 28.","DOI":"10.3390\/molecules28020776"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"207","DOI":"10.2147\/BTT.S472491","article-title":"Aspergillus Species from the Sabkha Marsh: Potential Antimicrobial and Anticancer Agents Revealed Through Molecular and Pharmacological Analysis","volume":"18","author":"Sajer","year":"2024","journal-title":"Biol. Targets Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2143","DOI":"10.1007\/s11172-019-2683-0","article-title":"Computer-aided prediction of biological activity spectra for organic compounds: The possibilities and limitations","volume":"68","author":"Poroikov","year":"2019","journal-title":"Russ. Chem. Bull."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"W432","DOI":"10.1093\/nar\/gkae298","article-title":"AdmetSAR3.0: A comprehensive platform for exploration, prediction and optimization of chemical ADMET properties","volume":"52","author":"Gu","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1080\/08927014.2024.2441259","article-title":"Zerumbone disrupts mixed biofilms of Candida albicans and Streptococcus mutans on acrylic resin","volume":"41","author":"Dias","year":"2025","journal-title":"Biofouling"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Lohse, M.B., Gulati, M., Craik, C.S., Johnson, A.D., and Nobile, C.J. (2020). Combination of Antifungal Drugs and Protease Inhibitors Prevent Candida albicans Biofilm Formation and Disrupt Mature Biofilms. Front. Microbiol., 11.","DOI":"10.3389\/fmicb.2020.01027"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Maione, A., de Alteriis, E., Carraturo, F., Galdiero, S., Falanga, A., Guida, M., Di Cosmo, A., Maselli, V., and Galdiero, E. (2021). The Membranotropic Peptide gH625 to Combat Mixed Candida albicans\/Klebsiella pneumoniae Biofilm: Correlation between In Vitro Anti-Biofilm Activity and In Vivo Antimicrobial Protection. J. Fungi, 7.","DOI":"10.3390\/jof7010026"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.archoralbio.2019.01.006","article-title":"Antifungal activities against Candida albicans, of cell-free supernatants obtained from probiotic Pediococcus acidilactici HW01","volume":"99","author":"Kim","year":"2019","journal-title":"Arch. Oral Biol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Balasubramanian, D., Schneper, L., Merighi, M., Smith, R., Narasimhan, G., Lory, S., and Mathee, K. (2012). The Regulatory Repertoire of Pseudomonas aeruginosa AmpC \u00df-Lactamase Regulator AmpR Includes Virulence Genes. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0034067"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1111\/jam.12701","article-title":"Antibiofilm potential of flavonoids extracted from Moringa oleifera seed coat against Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans","volume":"118","author":"Onsare","year":"2015","journal-title":"J. Appl. Microbiol."},{"key":"ref_40","unstructured":"Andrade, C.G.d. (2018). Efeito da Terapia Fotodin\u00e2mica Associada a Zincoporfirinas sobre Leishmania braziliensis. [Ph.D. Thesis, Universidade Federal de Pernambuco]."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1111\/j.1751-1097.2012.01076.x","article-title":"Combinational Sensitization of Leishmania with Uroporphyrin and Aluminum Phthalocyanine Synergistically Enhances their Photodynamic Inactivation in vitro and in vivo","volume":"88","author":"Dutta","year":"2012","journal-title":"Photochem. Photobiol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Abdallah, R.M., Hasan, H.E., and Hammad, A. (2024). Predictive modeling of skin permeability for molecules: Investigating FDA-approved drug permeability with various AI algorithms. PLoS Digit Health, 3.","DOI":"10.1371\/journal.pdig.0000483"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e202300395","DOI":"10.1002\/cmdc.202300395","article-title":"Design Principles for Balancing Lipophilicity and Permeability in beyond Rule of 5 Space","volume":"19","year":"2024","journal-title":"ChemMedChem"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1080\/17460441.2023.2275617","article-title":"Evaluating physiochemical properties of FDA-approved orally administered drugs","volume":"19","author":"Reese","year":"2024","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.addr.2012.10.009","article-title":"Detailed modeling of skin penetration\u2014An overview","volume":"65","author":"Naegel","year":"2013","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"199","DOI":"10.5599\/admet.2.4.147","article-title":"Linear combination methods for prediction and interpretation of drug skin permeation","volume":"2","author":"Scheler","year":"2015","journal-title":"ADMET DMPK"},{"key":"ref_47","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_48","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.1093\/jac\/dkw012","article-title":"Drug permeation and barrier damage in Leishmania-infected mouse skin","volume":"71","author":"Yardley","year":"2016","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/s40262-017-0570-0","article-title":"Clinical Pharmacokinetics of Systemically Administered Antileishmanial Drugs","volume":"57","author":"Kip","year":"2018","journal-title":"Clin. Pharmacokinet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1016\/j.drudis.2016.02.005","article-title":"Quantifying the Chameleonic Properties of Macrocycles and other High Molecular Weight Drugs","volume":"21","author":"Whitty","year":"2016","journal-title":"Drug Discov. Today"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"91","DOI":"10.25259\/SNI_184_2023","article-title":"Goodman and Gilman\u2019s The Pharmacological Basis of Therapeutics","volume":"14","author":"Khonsary","year":"2023","journal-title":"Surg. Neurol. Int."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Markovic, M., Zur, M., Garsiani, S., Porat, D., Cviji\u0107, S., Amidon, G.L., and Dahan, A. (2022). The Role of Paracellular Transport in the Intestinal Absorption and Biopharmaceutical Characterization of Minoxidil. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14071360"},{"key":"ref_53","unstructured":"Ridgway, N.D., and McLeod, R.S. (2015). Biochemistry of Lipids, Lipoproteins and Membranes, Elsevier Science. [6th ed.]."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Xiu, F., Rausch, M., Gai, Z., Su, S., Wang, S., and Visentin, M. (2023). The Role of Organic Cation Transporters in the Pharmacokinetics, Pharmacodynamics and Drug\u2013Drug Interactions of Tyrosine Kinase Inhibitors. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24032101"},{"key":"ref_55","unstructured":"Brunton, L.L., and Knollmann, B.C. (2025). As Bases Farmacol\u00f3gicas da Terap\u00eautica de Goodman e Gilman, Artmed. [14th ed.]."},{"key":"ref_56","unstructured":"Alberts, B., Heald, R., Johnson, A., Morgan, D., and Raff, M. (2022). Molecular Biology of the Cell, W. W. Norton & Company. [7th ed.]."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.redox.2014.11.008","article-title":"Molecular mechanisms of the microsomal mixed function oxidases and biological and pathological implications","volume":"4","author":"Cederbaum","year":"2014","journal-title":"Redox Biol."},{"key":"ref_58","first-page":"118","article-title":"Cytochrome p450 genetic polymorphisms and cancer","volume":"5","author":"Santos","year":"2004","journal-title":"Sa\u00fade Ci\u00eanc. A\u00e7\u00e3o"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2254","DOI":"10.2174\/15680266113136660158","article-title":"The evolution of cytochrome P450 enzymes as biocatalysts in drug discovery and development","volume":"13","author":"Gillam","year":"2013","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_60","first-page":"2202","article-title":"Drug Interactions and Their Mechanisms: A Comprehensive Review","volume":"8","author":"Nivetha","year":"2023","journal-title":"Int. J. Pharm. Res. Appl."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.pharmthera.2012.12.007","article-title":"Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation","volume":"138","author":"Zanger","year":"2013","journal-title":"Pharmacol. Ther."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Fairuz, S., Nair, R.S., and Billa, N. (2022). Orally Administered Amphotericin B Nanoformulations: Physical Properties of Nanoparticle Carriers on Bioavailability and Clinical Relevance. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14091823"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1080\/17460441.2021.1961741","article-title":"An update on the importance of plasma protein binding in drug discovery and development","volume":"16","author":"Di","year":"2021","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1007\/s12247-020-09462-0","article-title":"A Novel Method for Preparing Uniform-Sized PLGA Microspheres and the Application in Anti-tubercular Drug Delivery","volume":"16","author":"Lei","year":"2021","journal-title":"J. Pharm. Innov."},{"key":"ref_65","unstructured":"Mbi Feh, M.K., Patel, P., and Wadhwa, R. (2025). Clomiphene. StatPearls, StatPearls Publishing."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Fr\u00e9zard, F., Aguiar, M.M.G., Ferreira, L.A.M., Ramos, G.S., Santos, T.T., Borges, G.S.M., Vallejos, V.M.R., and De Morais, H.L.O. (2022). Liposomal Amphotericin B for Treatment of Leishmaniasis: From the Identification of Critical Physicochemical Attributes to the Design of Effective Topical and Oral Formulations. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15010099"},{"key":"ref_67","unstructured":"Aronson, J.K. (2016). Clomiphene. Meyler\u2019s Side Effects of Drugs, Elsevier."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1590\/S0034-70942012000200010","article-title":"Topical analgesics","volume":"62","author":"Flores","year":"2012","journal-title":"Rev. Bras. Anestesiol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1590\/S1984-82502011000100005","article-title":"Alternative methods in toxicity testing: The current approach","volume":"50","author":"Campos","year":"2014","journal-title":"Braz. J. Pharm. Sci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"100374","DOI":"10.1016\/j.comtox.2025.100374","article-title":"Conservative consensus QSAR approach for the prediction of rat acute oral toxicity","volume":"35","author":"Achar","year":"2025","journal-title":"Comput. Toxicol."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Iovine, N., Roncaglioni, A., and Benfenati, E. (2025). Predicting Acute Oral Toxicity in Bobwhite Quail: Development of QSAR Models for LD50. Environments, 12.","DOI":"10.3390\/environments12020056"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1093\/toxsci\/kfy152","article-title":"Machine Learning of Toxicological Big Data Enables Read-Across Structure Activity Relationships (RASAR) Outperforming Animal Test Reproducibility","volume":"165","author":"Luechtefeld","year":"2018","journal-title":"Toxicol. Sci."},{"key":"ref_73","first-page":"336","article-title":"Clomiphene citrate ameliorated lead acetate-induced reproductive toxicity in male Wistar rats","volume":"23","author":"Wahab","year":"2019","journal-title":"JBRA Assist. Reprod."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Liao, Y., Chang, Y.K., Wang, S.M., and Chang, H.C. (2022). Ceiling effect of clomiphene citrate on the testosterone to estradiol ratio in eugonadal infertile men. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0262924"},{"key":"ref_75","first-page":"28","article-title":"Efic\u00e1cia do citrato de clomifeno no tratamento do hipogonadismo hipogonadotr\u00f3fico: Uma revis\u00e3o de literatura","volume":"15","author":"Mariz","year":"2024","journal-title":"Rev. Pr\u00f3-UniverSUS"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/j.bjid.2013.11.013","article-title":"Kidney involvement in leishmaniasis\u2014A review","volume":"18","year":"2014","journal-title":"Braz. J. Infect. Dis."},{"key":"ref_77","first-page":"e20240138","article-title":"Visceral leishmaniasis in kidney transplant recipients and candidates: An integrative review of the last 20 years","volume":"47","author":"Neto","year":"2025","journal-title":"Braz. J. Nephrol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"306","DOI":"10.53986\/ibjm.2020.0054","article-title":"NQO1 enzyme and its role in cellular protection; an insight","volume":"2","author":"Atiaa","year":"2020","journal-title":"Iberoam. J. Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1038\/s41586-023-06710-4","article-title":"Tuning sterol extraction kinetics yields a renal-sparing polyene antifungal","volume":"623","author":"Maji","year":"2023","journal-title":"Nature"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1007\/s40203-024-00222-3","article-title":"Elucidating the structural basis for the enhanced antifungal activity of amide derivative against Candida albicans: A comprehensive computational investigation","volume":"12","author":"Kechi","year":"2024","journal-title":"Silico Pharmacol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.biochi.2024.08.007","article-title":"In silico-driven identification and experimental confirmation of antifungal proteins (AFPs) against Candida albicans","volume":"228","author":"Prusty","year":"2025","journal-title":"Biochimie"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"e1501240","DOI":"10.1126\/sciadv.1501240","article-title":"Regulation of protein-ligand binding affinity by hydrogen bond pairing","volume":"2","author":"Chen","year":"2016","journal-title":"Sci. Adv."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Madushanka, A., Moura, R.T., Verma, N., and Kraka, E. (2023). Quantum Mechanical Assessment of Protein\u2013Ligand Hydrogen Bond Strength Patterns: Insights from Semiempirical Tight-Binding and Local Vibrational Mode Theory. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24076311"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"162","DOI":"10.15446\/rcciquifa.v44n2.56291","article-title":"Molecular docking study of naturally-occurring compounds as inhibitors of N-myristoyl transferase towards antifungal agents discovery","volume":"44","author":"Bernal","year":"2015","journal-title":"Rev. Colomb. Cienc. Qu\u00edm.-Farm."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1007\/s12539-019-00327-w","article-title":"An Overview of Scoring Functions Used for Protein\u2013Ligand Interactions in Molecular Docking","volume":"11","author":"Li","year":"2019","journal-title":"Interdiscip. Sci. Comput. Life Sci."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"15003","DOI":"10.1039\/C7NJ03410E","article-title":"Complex interaction of caffeic acid with bovine serum albumin: Calorimetric, spectroscopic and molecular docking evidence","volume":"41","author":"Precupas","year":"2017","journal-title":"New J. Chem."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"24","DOI":"10.51847\/Une9jqjUCl","article-title":"Exploring Recent Updates on Molecular Docking: Types, Method, Application, Limitation & Future Prospects","volume":"13","author":"Sahu","year":"2024","journal-title":"Int. J. Pharm. Res. Allied Sci."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Phunyal, A., Adhikari, A., and Adhikari Subin, J. (2024). In silico exploration of potent flavonoids for dengue therapeutics. PLoS ONE, 19.","DOI":"10.1101\/2024.03.24.586491"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Timotheous, R., Naz, H., Arif, U., Dar, M.T., Sarwar, M.F., Awan, M.F., Ali, S., and Rab, S.O. (2025). Virtual screening assisted identification of a phytocompound as potent inhibitor against Candida lusitaniae; an in-silico study. BMC Infect. Dis., 25.","DOI":"10.1186\/s12879-024-10400-5"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"111629","DOI":"10.1016\/j.molbiopara.2024.111629","article-title":"Anti-Leishmania activity and molecular docking of unusual flavonoids-rich fraction from Arrabidaea brachypoda (Bignoniaceae)","volume":"259","author":"Nascimento","year":"2024","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1111\/andr.13388","article-title":"Clomiphene citrate for male infertility: A systematic review and meta-analysis","volume":"11","author":"Huijben","year":"2023","journal-title":"Andrology"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"e210401","DOI":"10.1590\/0074-02760210401","article-title":"Antioxidant defence system as a rational target for Chagas disease and Leishmaniasis chemotherapy","volume":"117","author":"Santi","year":"2022","journal-title":"Mem. Inst. Oswaldo Cruz"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Cavalheiro, M., and Teixeira, M.C. (2018). Candida Biofilms: Threats, challenges, and promising strategies. Front. Med., 5.","DOI":"10.3389\/fmed.2018.00028"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Iyer, K.R., Robbins, N., and Cowen, L.E. (2022). The role of Candida albicans stress response pathways in antifungal tolerance and resistance. iScience, 103953.","DOI":"10.1016\/j.isci.2022.103953"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"100111","DOI":"10.1016\/j.tcsw.2023.100111","article-title":"The role of the Candida biofilm matrix in drug and immune protection","volume":"10","author":"Roy","year":"2023","journal-title":"Cell Surf."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"5963","DOI":"10.1038\/s41598-026-36278-8","article-title":"Overcoming Candida albicans biofilm drug resistance via azole-sophorolipid synergy","volume":"16","author":"Jayasekara","year":"2026","journal-title":"Sci. Rep."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"6101","DOI":"10.1128\/AAC.00543-15","article-title":"Delicate Metabolic Control and Coordinated Stress Response Critically Determine Antifungal Tolerance of Candida albicans Biofilm Persisters","volume":"59","author":"Li","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Silva, S., Rodrigues, C.F., Ara\u00fajo, D., Rodrigues, M.E., and Henriques, M. (2017). Candida Species Biofilms\u2019 Antifungal Resistance. J. Fungi, 3.","DOI":"10.3390\/jof3010008"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Hwang, H.J., Li, D.d., Lee, J., Kang, M.K., Moon, H.R., and Lee, J.H. (2023). Compounds That Have an Anti-Biofilm Effect against Common Bacteria at Very Low Concentrations and Their Antibiotic Combination Effect. Antibiotics, 12.","DOI":"10.3390\/antibiotics12050853"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"15012","DOI":"10.1038\/npjbiofilms.2015.12","article-title":"A novel small molecule inhibitor of Candida albicans biofilm formation, filamentation and virulence with low potential for the development of resistance","volume":"1","author":"Pierce","year":"2015","journal-title":"npj Biofilms Microbiomes"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"100126","DOI":"10.1016\/j.bioflm.2023.100126","article-title":"Antifungal therapy of Candida biofilms: Past, present and future","volume":"5","author":"Ajetunmobi","year":"2023","journal-title":"Biofilm"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.2217\/fmb.13.101","article-title":"Mechanisms of Candida biofilm drug resistance","volume":"8","author":"Taff","year":"2013","journal-title":"Future Microbiol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"2182","DOI":"10.5455\/OVJ.2025.v15.i5.36","article-title":"Mechanism of recombinant 1,3-\u03b2-glucanase as antibiofilm to prevent antimicrobial resistance in antifungal therapy for vulvovaginitis candidiasis","volume":"15","author":"Masfufatun","year":"2025","journal-title":"Open Vet. J."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Wu, J., Jiang, C., Wang, H., Chen, T., Chen, X., and Da, W. (2026). The pathogenicity and future treatment strategies of Candida albicans. Front. Cell. Infect. Microbiol., 16.","DOI":"10.3389\/fcimb.2026.1752304"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.13005\/bbra\/3448","article-title":"Exploring New Antifungal Agents for the Treatment of Candida Infections in the Era of Resistance","volume":"4","author":"Bhatol","year":"2025","journal-title":"Biosci. Biotechnol. Res. Asia"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/8\/1133\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T04:11:05Z","timestamp":1785903065000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/8\/1133"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,3]]},"references-count":105,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["biom16081133"],"URL":"https:\/\/doi.org\/10.3390\/biom16081133","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,3]]}}}