Bioactive conformations of peptides and mimetics as milestones in drug design: Investigation of NK1 receptor antagonists

Nine potent and selective substance P receptor antagonists (NK1-) were analyzed with respect to their conformational space, with the aim to suggest probable conformations adopted at the receptor site and superposition rules for each structure (pharmacophore mapping). Key atoms within the ligands as well as receptor site points were considered in order to identify acceptable solutions (DISCO program). The results obtained allowed the suggestion or probable peptidic pharmacophores based on the structure of 1 (FK888). This knowledge was used to search commercial databases. The number and diversity of known retrieved NK1 antagonists allowed a general evaluation of the proposed pharmacophores. Moreover, a search in our proprietary database detected a short peptide with modest affinity but high selectivity for the NK1 receptor. The combination of molecular modeling with database searches is useful in a strategy aiming to develop new NK1 antagonists starting from existing knowledge.