Definition of New Pharmacophores for Nonpeptide Antagonists of Human Urotensin-II. Comparison with the 3D-structure of Human Urotensin-II and URP

Elodie Lescot , Jana Sopkova-de Oliveira Santos (1) , Christophe Dubessy (2) , Hassan Oulyadi (3) , Aurélien Lesnard (1) , Hubert Vaudry (4) , Ronan Bureau (1) , Sylvain Rault (1)

1 CERMN - Centre d'Etudes et de Recherche sur le Médicament de Normandie
2 Neuroendocrinologie cellulaire et moléculaire
3 COBRA - Chimie Organique et Bioorganique : Réactivité et Analyse
4 AHHBO - Asymétrie, hétérocycles, hétérochimie et bio-organique

Starting from nonpeptide agonists and antagonists of human urotensin-II (hU-II), several pharmacophores were designed and compared to the structure of hU-II. NMR and dynamic studies were realized on hU-II and urotensin-II-related peptide to check the conformation flexibilities of these peptides and the relationships between their potential 3D structures and the pharmacophores. In parallel, a virtual screening was carried out, leading to the discovery of six new derivatives with micromolar affinities. This last result shows the interest of these pharmacophores for the discovery of new ligands.

Domaines: Chemo-informatique; Pharmacologie; Chimie thérapeutique; Biologie structurale [q-bio.BM]

Elodie Lescot, Jana Sopkova-de Oliveira Santos, Christophe Dubessy, Hassan Oulyadi, Aurélien Lesnard, et al.. Definition of New Pharmacophores for Nonpeptide Antagonists of Human Urotensin-II. Comparison with the 3D-structure of Human Urotensin-II and URP. Journal of Chemical Information and Modeling, 2007, 47 (2), pp.602-612. ⟨10.1021/ci6003948⟩. ⟨hal-02179719⟩