In-Silico Screening Without Structural Comparisons:

Real Lead Hopping

Tim. Cheeseright, Mark Mackey, Andy Vinter

Cresset BioMolecular Discovery Ltd

Spirella Building, Bridge Road, Letchworth SG6 4ET

Virtual screening for new hits and leads for GPCR and ion-channel projects is a process with few success stories. The lack of xray data prevents the most common ‘docking’ methods from working and most ligand-based methods fail to find completely new structural classes.

We will give details of a new method of describing ligands. This field technology represents ligands in terms of the electron cloud that they present to the receptor.  The surface and shape properties of a molecule are described as ‘field points’. Comparison of the field point patterns of different ligands that bind at the same receptor can give a putative binding conformation. Furthermore these patterns can be combined with a similarity metric allowing molecules’ field properties to be rapidly compared.  Population of a database with commercially available compounds and comparison of a known active to the database allows virtual screening using fields to be applied to lead discovery.

Validation on two peptide-ligand GPCR targets will be reported.  The majority of small-molecule hits had no structural similarity to any known inhibitor, demonstrating that this technique can find entirely novel structural motifs. Furthermore, useful hits were retrieved from carefully chosen fragments of a large peptide agonist.