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After the crystal structure of MmpL3 from <jats:italic>Mycobacterium smegmatis<\/jats:italic> in complex with SQ109 became available, it was suggested that SQ109 inhibits Mmpl3 mycolic acid transporter. Here, we showed using molecular dynamics (MD) simulations that the binding profile of nine SQ109 analogs\u00a0with\u00a0inhibitory\u00a0potency against Mtb and\u00a0alkyl or aryl adducts at C-2 or C-1 adamantyl carbon to MmpL3 was consistent with the X-ray structure of MmpL3 \u2013 SQ109 complex. We showed that rotation of SQ109 around carbon\u2013carbon bond in the monoprotonated ethylenediamine unit favors two <jats:italic>gauche<\/jats:italic> conformations as minima in water and lipophilic solvent using DFT calculations as well as inside the transporter\u2019s binding area using MD simulations. The binding assays in micelles suggested that the binding affinity of the SQ109 analogs was increased for the larger, more hydrophobic adducts, which was consistent with our results from MD simulations of the SQ109 analogues suggesting that sizeable C-2 adamantyl adducts of SQ109 can fill a lipophilic region between Y257, Y646, F260 and F649 in MmpL3. This was confirmed quantitatively by our calculations of the relative binding free energies using the thermodynamic integration coupled with MD simulations method with a mean assigned error of 0.74\u00a0kcal\u00a0mol<jats:sup>\u22121<\/jats:sup> compared to the experimental values.<\/jats:p>\n                <jats:p><jats:bold>Graphical abstract<\/jats:bold><\/jats:p>","DOI":"10.1007\/s10822-023-00504-6","type":"journal-article","created":{"date-parts":[[2023,5,2]],"date-time":"2023-05-02T08:02:57Z","timestamp":1683014577000},"page":"245-264","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Study of SQ109 analogs binding to mycobacterium MmpL3 transporter using MD simulations and alchemical relative binding free energy calculations"],"prefix":"10.1007","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0144-4792","authenticated-orcid":false,"given":"Marianna","family":"Stampolaki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6974-2561","authenticated-orcid":false,"given":"Ioannis","family":"Stylianakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8929-4727","authenticated-orcid":false,"given":"Helen I.","family":"Zgurskaya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6110-1903","authenticated-orcid":false,"given":"Antonios","family":"Kolocouris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,5,2]]},"reference":[{"key":"504_CR1","doi-asserted-by":"publisher","first-page":"e265","DOI":"10.1016\/S2666-5247(21)00301-3","volume":"3","author":"TM Walker","year":"2022","unstructured":"Walker TM et al (2022) The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: a genotypic analysis. 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