Removing unnecessary atoms from compounds uncovered in preliminary drug screens could simplify the drug development process, say US researchers. With this in mind the American team has developed a method to identify the biologically active sections of these pharmaceutical leads.

The decreasing number of new drugs emerging from pharmaceutical pipelines is challenging medicinal chemists to cultivate fresh approaches to drug design and development. In response to this, Thomas Kodadek and co-workers at the University of Texas Southwestern Medical Center, in Dallas, US, developed their approach to identify the smallest active fragment - the minimal pharmacophore - of peptoid compounds. Peptoids are similar to peptides but with the side-chain connected to the nitrogen atom rather than the adjacent alpha-carbon. 

The group's method is based on glycine scanning, which compares a peptoid with analogues in which the nitrogen-linked side-chains are replaced with hydrogen. This deletion strategy quickly identifies the side-chains required for biological activity, allowing researchers to strip away any superfluous atoms. 

Using this technique, the team created a proteasome inhibitor that was five times more active than the parent molecule in cultured cells. The proteasome is a protein complex that degrades damaged proteins and its inhibitors have been used in chemotherapy to target blood cancers. The researchers attributed the inhibitor's improved activity to the removal of charged residues, which increased the peptoid's cell permeability.

Focusing on the minimal pharmacophore should simplify structure optimisation in drug development, said Kodadek. 'The aim is to quickly cut down the molecule to its essentials,' he explained, adding that 'the next step is to subtly change the essential side-chains to improve the fit of the molecule with the protein target and thus increase its potency.'

Russell Johnson