The bradykinin B2 receptor (B2R) represents a promising thus challenging target for the treatment of cardiovascular and inflammatory diseases. However, only few orally bioavailable ligands are known to date. The aim of this study is to discover novel B2 receptor antagonists by computer-aided drug design.Starting from two recently discovered B2R ligands (JSM102921-2 and MEN161323) extensive binding mode analyses were performed by means of homology modeling and molecular dynamics (MD) simulations. On the basis of this careful analysis, several chemical feature-based 3D pharmacophore models could be developed and retrospectively validated. Simultaneously, ligand conformations of JSM10292 were sampled by MD simulations in the protein. Representative frames yielded promising query conformations for shape-based virtual screening4. Combined chemical-feature and shape-based similarity searches were performed against a multi-conformational database of more than 7.1 million commercially available compounds. Screening work-flow, validation, experimental challenges and biological results will be presented and discussed. _______________________1Gibson, C, et al., Journal of Medicinal Chemistry, 2009., 2 Faussner, S., et al., British Journal of Pharmacology, 2012, 3Meini, S., et al., British Journal of Pharmacology, 2011., 4ROCS 3.2.0.4: OpenEye Scientific Software, Santa Fe, NM.

Novel bradykinin B2 receptor antagonists identified by virtual screening

248th National Meeting (2014)

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