STRUCTURE-BASED INHIBITOR DESIGN BY USING PROTEIN MODELS FOR THE DEVELOPMENT OF ANTIPARASITIC AGENTS

The lack of an experimentally determined structure of a target protein frequently limits the application of structure-based drug design meth ods. In an effort to overcome this limitation, we have investigated th e use of computer model-built structures for the identification of pre viously unknown inhibitors of enzymes from two major protease families , serine and cysteine proteases. We have successfully used our model-b uilt structures to identify computationally and to confirm experimenta lly the activity of nonpeptidic inhibitors directed against important enzymes in the schistosome [2-(4-methoxybenzoyl)-1-naphthoic acid, K(i ) = 3 muM] and malaria {oxalic bis[(2-hydroxy-1-naphthylmethylene)hydr azide], IC50 = 6 muM} parasite life cycles.