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 methods. In an effort to overcome this limitation, we have investigated the use of computer model-built structures for the identification of previously unknown inhibitors of enzymes from two major protease families, serine and cysteine proteases. We have successfully used our model-built structures to identify computationally and to confirm experimentally 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)hydrazide], IC50 = 6 muM} parasite life cycles.