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To alleviate this problem, a new class of antibacterials is urgently needed; recently, novel bacterial topoisomerase inhibitors (NBTIs) have been found to be particularly important. Based on 67 experimentally evaluated NBTIs against wild-type (WT) DNA gyrase originating from Staphylococcus aureus, a predictive QSAR model was initially constructed and validated and was later used for in silico prediction of biological activities for an in house designed compound library of 548 novel drug-like NBTI combinatorial analogs. To evaluate the influence of gyrA alterations on NBTI resistance, various mutant homology models were constructed; meanwhile, their resistance profiles were assessed and validated relative to that of WT enzyme by structure-based virtual screening (VS) of known NBTIs. Surprisingly, the M121K mutant model was recognized as the most selective due to an additional established cation\u2013\u03c0 interaction between K121-NH3+ (not found in the WT) and the aromatic moiety of the NBTI right-hand site (RHS) fragment; this finding was additionally supported by VS of our combinatorially generated NBTIs. Moreover, we identified several attractive, synthetically feasible RHS building blocks that may enable the development of new NBTIs.<\/jats:p>\n                  <jats:p\/>","DOI":"10.1039\/c7mb00168a","type":"journal-article","created":{"date-parts":[[2017,5,23]],"date-time":"2017-05-23T09:24:41Z","timestamp":1495531481000},"page":"1406-1420","update-policy":"https:\/\/doi.org\/10.1039\/rsc_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Structure-based design of novel combinatorially generated NBTIs as potential DNA gyrase inhibitors against various\n                    <i>Staphylococcus aureus<\/i>\n                    mutant strains"],"prefix":"10.1093","volume":"13","author":[{"given":"Anja","family":"Kolaric","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana b , A\u0161ker\u010deva 7, 1000 Ljubljana Slovenia"},{"name":"Department of Cheminformatics, National Institute of Chemistry a , Hajdrihova 19, 1000 Ljubljana Slovenia \u00a0 nikola.minovski@ki.si \u00a0 +386 1 4760 300 \u00a0 +386 1 4760 383"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0039-2246","authenticated-orcid":false,"given":"Nikola","family":"Minovski","sequence":"additional","affiliation":[{"name":"Department of Cheminformatics, National Institute of Chemistry a , Hajdrihova 19, 1000 Ljubljana Slovenia \u00a0 nikola.minovski@ki.si \u00a0 +386 1 4760 300 \u00a0 +386 1 4760 383"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2017,5,23]]},"reference":[{"key":"2026010816055764300_cit1"},{"key":"2026010816055764300_cit2","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1146\/annurev.biochem.70.1.369","volume":"70","author":"Champoux","year":"2001","journal-title":"Annu. 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