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Secondary interactions fine\u2010tune tight binding in regions of the active site cavity &gt;5 \u00c5 away from zinc, and this work highlights three such features: (1) advantageous conformational restraints of a bicyclic thienothiazene\u20106\u2010sulfonamide\u20101,1\u2010dioxide inhibitor skeleton in comparison with a monocyclic 2,5\u2010thiophenedisulfonamide skeleton; (2) optimal substituents attached to a secondary sulfonamide group targeted to interact with hydrophobic patches defined by Phe131, Leu198, and Pro202; and (3) optimal stereochemistry and configuration at the C\u20104 position of bicyclic thienothiazene\u20106\u2010sulfonamides; the C\u20104 substituent can interact with His64, the catalytic proton shuttle. Structure\u2010activity relationships rationalize affinity trends observed during the development of brinzolamide (Azopt<jats:sup>TM<\/jats:sup>), the newest carbonic anhydrase inhibitor approved for the treatment of glaucoma.<\/jats:p>","DOI":"10.1002\/pro.5560071201","type":"journal-article","created":{"date-parts":[[2009,2,10]],"date-time":"2009-02-10T06:15:58Z","timestamp":1234246558000},"page":"2483-2489","source":"Crossref","is-referenced-by-count":87,"title":["Structural analysis of inhibitor binding to human carbonic anhydrase II"],"prefix":"10.1002","volume":"7","author":[{"given":"P. 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