pharmacophore model

A pharmacophore model is a three-dimensional sketch of what a molecule needs in order to be active, stripped of any particular chemistry. Think of it as a wanted poster that says, in effect, an active molecule must have a positive charge here, a ring that can stack there, and a hydrogen-bond donor at this distance, without saying which exact atoms provide them.

Each requirement is a pharmacophore feature, such as a hydrogen-bond donor or acceptor, a positive or negative charge, an aromatic ring, or a hydrophobic group, placed at a specific point in space with a tolerance. The set of these features, and the geometric distances between them, defines the model. It can be built from a single known protein-ligand complex or by overlaying several active molecules to find what they share.

Once defined, the model becomes a query for searching databases: any molecule whose flexible conformations can place the right features in the right places is a candidate, even if it has a completely different scaffold. This makes pharmacophore searching a fast route to scaffold-hopping. The caveat is that a sloppy or overly loose model retrieves many false hits, while an overly tight one misses real ones, so building and validating the model is the hard part.