This blog explores pharmacophores, their role in drug discovery, and how to perform a pharmacophore based search.
What is a pharmacophore?
A pharmacophore is a spatial collection of steric and electronic features which are necessary to a molecule's interactions.
Put simply; a pharmacophore maps out
why ligand X binds to protein Y in terms of fundamental chemical characteristics.
By viewing the protein-ligand binding in these terms, it becomes easier to find alternative ligands that would achieve the same end result.
The pharmacophore of a molecule maps out the key electronic and steric features that are essential to its interactions. Here spheres mark out the key features on a molecule in CSD-CrossMiner.
How can pharmacophore search support drug discovery?
Viewing ligand-protein binding as its fundamental features in a pharmacophore, we can;
Remove human bias or preconceptions
Automate searches for alternative molecules
Spot patterns of interactions which may help or hinder our work
Identify possible cross-reactivity (other proteins that may bind our ligand)
Search for alternatives to a natural ligand, where no protein structure is available (e.g. when a target protein is disordered)
How to perform a pharmacophore based search?
It's possible to create and edit a pharmacophore then search against databases of structures using
By default you can search the Protein Data Bank and the
Cambridge Structural Database - but you can also search in-house databases where required.
Learn how to set up and run a pharmacophore based search in this 5 minute video.