Conformational analysis of pseudo-peptides: The case of FK888, a potent and selective substance P receptor antagonist

Molecular recognition is a central problem in medicinal sciences, and therefore a knowledge of the salient molecular features neccessary for efficient interaction with a receptor as well as their relative spatial arrangement is of crucial importance. Thus, an insight into probable biorelevant 3D structures by conformational analysis is equally fundamental. In the present study, we describe the conformational analysis of FK888, a potent and selective pseudo-peptide antagonist of the NK1 receptor of substance P, using an in-house developed method (CONFEX: CONFormational EXploration). Conformations could be subdivided into four families according to peptidic folding: the first two present an extended conformation which can be characterized as a hairpin-like structure, while the other two present a β-turn-like arrangement. These results were compared with experimental findings obtained by NMR spectroscopy.