Bioactive conformation ofstromelysin inhibitors determined by transferred nuclear Overhauser effects

Thetransferred nuclear Overhauser effect has beenusedtodetermine thebiologically active conformations of twostromelysin inhibitors. Bothinhibitors usedinthis study werehydroxamic acids generated viachemical synthesis. These structures, representing theconformation ofeachinhibitor boundtostromelysin, superimposed withexcellent agreement. Thestudy also provided information ontheshape andorienta- tionoftheS2'andSi'pockets oftheenzymerelative to thermolysin. Comparisons weremadebetween stromelysin and thermolysin inhibitors tocritically examine thermolysin asa template forstromelysin-inhi bitor design. Theenzyme-bound conformations ofthese stromelysin inhibitors weredetermined foruseasatemplate inconformationally restricted drugdesign. Stromelysin 1isazinc metalloendoproteinase