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Recently, we reported that <jats:italic>Candida albicans<\/jats:italic> Bdf1, a bromodomain and extra\u2010terminal domain (BET) bromodomain with paired acetyl\u2010lysine (AcK) binding sites (BD1 and BD2) is essential for fungal cell growth and that an imidazopyridine (<jats:bold>1<\/jats:bold>) binds to BD2 with selectivity versus both BD1 and human BET bromodomains. Bromodomain binding pockets contain a conserved array of structural waters. Molecular dynamics simulations now reveal that one water molecule is less tightly bound to BD2 than to BD1, explaining the site selectivity of <jats:bold>1<\/jats:bold>. This insight is useful in the performance of ligand docking studies to guide design of more effective Bdf1 inhibitors, as illustrated by the design of 10 new imidazopyridine BD2 ligands <jats:bold>1a\u2013j<\/jats:bold>, for which experimental binding and site selectivity data are presented.<\/jats:p>","DOI":"10.1002\/jcc.26997","type":"journal-article","created":{"date-parts":[[2022,10,3]],"date-time":"2022-10-03T16:06:36Z","timestamp":1664813196000},"page":"2121-2130","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Toward more potent imidazopyridine inhibitors of <scp><i>Candida albicans<\/i><\/scp> Bdf1: Modeling the role of structural waters in selective ligand binding"],"prefix":"10.1002","volume":"43","author":[{"given":"Yingsheng","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Chemistry University of Southern California  Los Angeles California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Justin M.","family":"Overhulse","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Southern California  Los Angeles California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathan J.","family":"Dupper","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Southern California  Los Angeles California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanchun","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Southern California  Los Angeles California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Boris A.","family":"Kashemirov","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Southern California  Los Angeles California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaiyao","family":"Wei","sequence":"additional","affiliation":[{"name":"Univ. 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