Based upon the crystal structure of a previously reported fragment hit that binds to Corresponding author. β-secretase, a novel series of non-peptidic small-molecule β-secretase inhibitors, namely hexahydropyrimidin-5-ols, along with two series of their analogues, were rationally designed through structural modification. The CADD study was performed and revealed good expectation. Inhibitory activities of the corresponding structural cores were tested, which provided further support for our design approach.
Computer aided fragment-based lead discovery has been successfully applied to the design of inhibitors of aspartyl protease enzyme β-secretase（BACE1）.A benzimidamide fragment,which binds to the two catalytic aspartic acid residues in the active site of the enzyme,was selected as the starting compound.A novel series of 3-phenethylbenzimidamide inhibitors were designed and synthesized.Although biological evaluation results showed that the compounds displayed poor inhibitory activity towards BACE1,3-phenethylbenzimidamide analogs might be modified as potential BACE1 inhibitors.
A novel series of pyrrolidinone analogs that are designed as Michael addition acceptors to react irreversibly with the proteasome active site Thr1O~γhave been synthesized.Although biological evaluation results show that the compounds display poor inhibitory activity towards the proteasome active sites,pyrrolidinone analogs might still be modified to be potential 20S proteasome inhibitors.
