Carbonic anhydrase inhibitors molecular modeling

At Merck, the structure-based design of carbonic anhydrase inhibitors was started in the mid-1980s. The first compound with molecular modeling and X-ray structure determination playing an important role in the discovery process was thienothiopyrane-sulfonamide 20 (MK-927). This binds to carbonic anhydrase with a subnanomolar binding constant (Xi = 0.7 nM). 

Another approach to representing the metal center in a molecular-mechanics-based model has been developed for zinc(II) centers and apphed to the modeling of the interaction of natural substrates and inhibitors of the enzyme human carbonic anhydrase [157, 492, 493]. Stmcturally characterized four-, five- and six-coordinate small-molecule complexes of zinc(II) were analyzed to determine the distribution of bond lengths and angles about the zinc ion. A function was developed that was able to reproduce these structural features, and was added to the program YETI [494], developed for modeling smaU-molecule-metalloprotein interactions. 

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