The use of ligand-based de novo design for scaffold hopping and sidechain optimization: two case studies.

This paper describes the application of de novo design utilizing exclusively ligand information. In the current approach, ligand design criteria, including pharmacophores, similarity and desired properties are applied as part of a fitness function driving the design process, instead of using them as filters after the process. This allows relevant parts of chemical space to be explored more efficiently. Two case studies of successful ligand design are also presented, one aimed at scaffold hopping, the other for exploring substitution patterns around a novel scaffold.

NMR structural characterization of a minimal peptide antagonist bound to the extracellular domain of the corticotropin-releasing factor1 receptor.

Natural peptide agonists of corticotrophin-releasing factor (CRF) receptors bind to the receptor by a two-site mechanism as follows: the carboxyl end of the ligand binds the N-terminal extracellular domain (ECD) of the receptor and the amino portion of the ligand binds the extracellular face of the seven transmembrane region. Recently, peptide antagonists homologous to the 12 C-terminal residues of CRF have been derived, which bind the CRF(1) receptor through an interaction with the ECD. Here we characterized the binding of a minimal 12-residue peptide antagonist while bound to the isolated ECD of the CRF(1) receptor. We have expressed and purified soluble and properly folded ECD independent from the seven-transmembrane region as a thioredoxin fusion protein in Escherichia coli. A model of the peptide antagonist, cyclic corticotrophin-releasing factor residues 30-41 (cCRF(30-41)), was calculated while bound to the recombinant ECD using transferred nuclear Overhauser effect spectroscopy. Although the peptide is unstructured in solution, it adopts an alpha-helical conformation when bound to the ECD. Residues of cCRF(30-41) comprising the binding interface with the ECD were mapped using saturation transfer difference NMR. Two hydrophobic residues (Met(38) and Ile(41)) as well as two amide groups (Asn(34) and the C-terminal amide) on one face of the helix defined the binding epitope of the antagonist. This epitope may be used as a starting point for development of non-peptide antagonists targeting the ECD of this receptor.

The use of consensus scoring in ligand-based virtual screening.

A new consensus approach has been developed for ligand-based virtual screening. It involves combining highly disparate properties in order to improve performance in virtual screening. The properties include structural, 2D pharmacophore and property-based fingerprints, scores derived using BCUT descriptors, and 3D pharmacophore approaches. Different approaches for the combination of all or some of these methods have been tested. Logistic regression and sum ranks were found to be the most advantageous in different pharmaceutical applications. The three major reasons consensus scoring appears to enrich data sets better than single scoring functions are (1) using multiple scoring functions is similar to repeated samplings, in which case the mean is closer to the true value than any single value, (2) due to the better clustering of actives, multiple sampling will recover more actives than inactives, and (3) different methods seem to agree more on the ranking of the actives than on the inactives. Furthermore, consensus results are not only better but are also more consistent across receptor systems.