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The presence and\/or position of a single methyl substituent drastically alters inhibitor potency and can result in coordination modes not observed in small-molecule model complexes. It is shown that this unexpected binding mode is the result of a steric clash between the methyl group and a highly ordered water network in the active site that is further stabilized by the formation of a hydrogen bond and favorable hydrophobic contacts. The affinity of MBPs is dependent on a large number of factors including donor atom identity, orientation, electrostatics, and van der Waals interactions. These results suggest that metal coordination by metalloenzyme inhibitors is a malleable interaction and that it is thus more appropriate to consider the metal-binding motif of these inhibitors as a pharmacophore rather than a \u201cchelator\u201d. The rational design of inhibitors targeting metalloenzymes will benefit greatly from a deeper understanding of the interplay between the variety of forces governing the binding of MBPs to active site metal ions.<\/jats:p>","DOI":"10.1021\/jm500984b","type":"journal-article","created":{"date-parts":[[2014,8,12]],"date-time":"2014-08-12T14:42:12Z","timestamp":1407854532000},"page":"7126-7135","source":"Crossref","is-referenced-by-count":34,"title":["Exploring the Influence of\nthe Protein Environment\non Metal-Binding Pharmacophores"],"prefix":"10.1021","volume":"57","author":[{"given":"David P.","family":"Martin","sequence":"first","affiliation":[{"name":"University of California, San Diego , , 9500 Gilman Drive, MC 0358 , , ,","place":["La Jolla, California, United States, 92093"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick G.","family":"Blachly","sequence":"additional","affiliation":[{"name":"University of California, San Diego , , 9500 Gilman Drive, MC 0358 , , ,","place":["La Jolla, California, United States, 92093"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Andrew","family":"McCammon","sequence":"additional","affiliation":[{"name":"University of California, San Diego , , 9500 Gilman Drive, MC 0358 , , ,","place":["La Jolla, California, United States, 92093"]},{"name":"University of California, San Diego , , 9500 Gilman Drive, MC 0358 , , ,","place":["La Jolla, California, United States, 92093"]},{"name":"University of California, San Diego , , 9500 Gilman Drive, MC 0358 , , ,","place":["La Jolla, California, United States, 92093"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seth M.","family":"Cohen","sequence":"additional","affiliation":[{"name":"University of California, San Diego , , 9500 Gilman Drive, MC 0358 , , ,","place":["La Jolla, California, United States, 92093"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,8,12]]},"reference":[{"key":"2026090201205831500_cit1","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1039\/b617121b","article-title":"Zinc Metalloproteins\nas Medicinal Targets","volume":"37","author":"Anzellotti","year":"2008","journal-title":"Chem. 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