[摘要]：Selective inhibition of neuronal nitric oxide synthase (nNOS) has been shown to prevent brain injury and is important for the treatment of various neurodegenerative disorders. This study shows that not only greater inhibitory potency and isoenzyme selectivity but more druglike properties can be achieved by fragment hopping. On the basis of the structure of lead mol. 6, fragment hopping effectively extd. the minimal pharmacophoric elements in the active site of nNOS for ligand hydrophobic and steric interactions and generated appropriate lipophilic fragments for lead optimization. More potent and selective inhibitors with better druglike properties were obtained within the design of 20 derivs. Our structure-based inhibitor design for nNOS and SAR anal. reveal the robustness and efficiency of fragment hopping in lead discovery and structural optimization, which implicates a broad application of this approach to many other therapeutic targets for which known druglike small-mol. modulators are still limited.
