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Clinical trials have shown the efficacy of herbal formulations containing\n                    <jats:italic>Nicotiana tabacum<\/jats:italic>\n                    ,\n                    <jats:italic>Mangifera indica<\/jats:italic>\n                    ,\n                    <jats:italic>Carica papaya<\/jats:italic>\n                    , and\n                    <jats:italic>Solanum rugosum<\/jats:italic>\n                    , although the active phytochemicals remain unstudied. In the present study, we employed an\n                    <jats:italic>in silico<\/jats:italic>\n                    approach to identify the active phytochemicals from these plants that could inhibit\n                    <jats:italic>M. ulcerans<\/jats:italic>\n                    dihydrofolate reductase (\n                    <jats:italic>Mu<\/jats:italic>\n                    DHFR), a crucial enzyme for mycobacterial survival. A library of 172 phytochemicals was screened using molecular docking, followed by 300\u2010ns molecular dynamics (MD) simulations using AMBER for the top hits and standard drugs (methotrexate and trimethoprim). Binding free energies were calculated using the molecular mechanics\/generalized born surface area (MM\/GBSA) method. The extended MD simulations and post hoc MM\/GBSA analysis revealed that kaempferol\u20103\u2010O\u2010rutinoside (\n                    <jats:italic>\u0394<\/jats:italic>\n                    <jats:italic>G<\/jats:italic>\n                    <jats:sub>bind<\/jats:sub>\n                    \u221251.62\u2009kcal\/mol) and neochlorogenic acid (\n                    <jats:italic>\u0394<\/jats:italic>\n                    G\n                    <jats:sub>bind<\/jats:sub>\n                    \u221249.44\u2009kcal\/mol) exhibited the strongest and most stable binding to\n                    <jats:italic>Mu<\/jats:italic>\n                    DHFR. The binding energies were more favorable than both methotrexate (\n                    <jats:italic>\u0394<\/jats:italic>\n                    <jats:italic>G<\/jats:italic>\n                    <jats:sub>bind<\/jats:sub>\n                    \u221244.18\u2009kcal\/mol) and trimethoprim (\n                    <jats:italic>\u0394<\/jats:italic>\n                    <jats:italic>G<\/jats:italic>\n                    <jats:sub>bind<\/jats:sub>\n                    \u221241.01\u2009kcal\/mol) used as positive controls. Stability analyses (RMSD and RMSF) and principal component analysis (PCA) confirmed that these compounds form stable complexes and induce specific conformational states in the enzyme. Favorable ADMET profiles, particularly the lack of predicted skin sensitization, support their potential for topical use. This study identifies kaempferol\u20103\u2010O\u2010rutinoside and neochlorogenic acid as the most promising lead candidates for developing novel BU therapies, warranting their prioritization for experimental validation.\n                  <\/jats:p>","DOI":"10.1155\/bmri\/4196295","type":"journal-article","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T13:08:03Z","timestamp":1756904883000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["In Silico Investigation of Phytochemicals From Clinically Tested Herbal Extracts as Potential Dihydrofolate Reductase Inhibitors for Buruli Ulcer"],"prefix":"10.1155","volume":"2025","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-1610-8531","authenticated-orcid":false,"given":"Alkhair Adam Khalil","family":"Mohamed","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1063-5114","authenticated-orcid":false,"given":"Tamekloe","family":"Woasiedem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5319-4518","authenticated-orcid":false,"given":"Philip Collins","family":"Appiah-Ofori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6405-0963","authenticated-orcid":false,"given":"Esraa Mohammed Abdulmahmoud","family":"Adam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5891-2886","authenticated-orcid":false,"given":"Samuel Asiamah","family":"Obiri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5037-0777","authenticated-orcid":false,"given":"Lawrence Sheringham","family":"Borquaye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4341-3361","authenticated-orcid":false,"given":"Christian K.","family":"Adokoh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0621-9057","authenticated-orcid":false,"given":"Ghazi","family":"Elamin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3451-4379","authenticated-orcid":false,"given":"Isaac","family":"Asiamah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,3]]},"reference":[{"key":"e_1_2_9_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2023.e22018"},{"key":"e_1_2_9_2_2","unstructured":"WHO The Global Health Observatory: Buruli Ulcer 2024 Retrieved 06\/08\/2024 fromhttps:\/\/www.who.int\/data\/gho\/data\/themes\/topics\/buruli-ulcer#:%7E:text=Buruli%2520ulcer%2520has%2520been%2520reported from%2520the%2520Western%2520Pacific%2520Region."},{"key":"e_1_2_9_3_2","doi-asserted-by":"publisher","DOI":"10.1080\/17512433.2020.1752663"},{"key":"e_1_2_9_4_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmjgh-2022-010813"},{"key":"e_1_2_9_5_2","first-page":"52","article-title":"Therapeutic Survey on Traditional Treatment of Buruli Ulcer in C\u00f4te D\u2019ivoire","volume":"4","author":"Tr\u00e9bissou J. 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