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We applied a battery of heterogeneous computational resources, encompassing two in\u2010house tools described here for the first time, to (a) assess the druggability potential of AP4M1, (b) characterize SPG50\u2010associated mutations and their 3D scenario, (c) identify mutation\u2010tailored drug candidates for SPG50, and (d) elucidate their mechanisms of action by means of structural considerations on homology models of the adapter protein complex 4 core. Altogether, the collected results indicate R367Q as the mutation with the most promising potential of being corrected by small\u2010molecule drugs, and the flavonoid rutin as best candidate for this purpose. Rutin shows promise in rescuing the interaction between the AP4M1 and adapter protein complex subunit beta\u20101 (AP4B1) subunits by means of a glue\u2010like mode of action. Overall, this approach offers a framework that could be systematically applied to the investigation of mutation\u2010wise molecular mechanisms in different hereditary spastic paraplegias, too.<\/jats:p>","DOI":"10.1002\/pro.70006","type":"journal-article","created":{"date-parts":[[2024,12,26]],"date-time":"2024-12-26T13:14:44Z","timestamp":1735218884000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Restoring adapter protein complex 4 function with small molecules: an in silico approach to <scp>spastic paraplegia 50<\/scp>"],"prefix":"10.1002","volume":"34","author":[{"given":"Serena","family":"Francisco","sequence":"first","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences University of Torino  Torino Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorenzo","family":"Lamacchia","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences University of Torino  Torino Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Attilio","family":"Turco","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences University of Torino  Torino Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppe","family":"Ermondi","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences University of Torino  Torino Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giulia","family":"Caron","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences University of Torino  Torino Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9925-1904","authenticated-orcid":false,"given":"Matteo","family":"Rossi Sebastiano","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences University of Torino  Torino Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,12,26]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku1205"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.3779"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.145.5.923"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI170226"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-10-S8-S8"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2010.01.015"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.1c00201"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.2235"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI164575"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adg7492"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.7529940"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)00735-3"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2015.07.004"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/1472-6807-13-S1-S11"},{"key":"e_1_2_7_16_1","first-page":"e1676","article-title":"Ligandability and druggability assessment via machine learning. 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