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With the intent of discovering novel molecular scaffolds for designing protease inhibitors, the computer program GrowMol was used to generate peptidemimetic inhibitors of aspartic proteases. Beginning with the X-ray crystal structure of A66702 complexed to pepsin, GrowMol successfully generated a series of known cyclic inhibitors of pepsin in which the cysteine side chains in the P1 and P3 inhibitor subsites are connected. GrowMol also created a series of novel urea-derived inhibitors of pepsin, a series of ?,?-disubstituted amino-alcohol-derived structures, and a series of cyclohexanol-derived inhibitors in which the core portion of the inhibitor lacks nitrogen. The paper describes the iterative process of selection and synthesis of computer-generated structure, determination of activity, and reassessment of potency with respect to the beginning crystal structure. These efforts led to the synthesis of analogs 9–12 which are novel pepsin inhibitors with moderate inhibitory activity. Attempts to crystallize these inhibitors in the active site of pepsin to determine if compounds 9–12 bind as predicted by GrowMol are in progress.

With the intent of discovering novel molecular scaffolds for designing protease inhibitors, the computer program GrowMol was used to generate peptidemimetic inhibitors of aspartic proteases. Beginning with the X-ray crystal structure of A66702 complexed to pepsin, GrowMol successfully generated a series of known cyclic inhibitors of pepsin in which the cysteine side chains in the P1 and P3 inhibitor subsites are connected. GrowMol also created a series of novel urea-derived inhibitors of pepsin, a series of ?,?-disubstituted amino-alcohol-derived structures, and a series of cyclohexanol-derived inhibitors in which the core portion of the inhibitor lacks nitrogen. The paper describes the iterative process of selection and synthesis of computer-generated structure, determination of activity, and reassessment of potency with respect to the beginning crystal structure. These efforts led to the synthesis of analogs 9–12 which are novel pepsin inhibitors with moderate inhibitory activity. Attempts to crystallize these inhibitors in the active site of pepsin to determine if compounds 9–12 bind as predicted by GrowMol are in progress.