Using scaffold hopping to search nearby chemical space

How Can Computational Chemistry Help Find New Drugs from Old?

In this series of blogs, Dr Robert Scoffin, CEO of Cresset, explores how computational chemistry is being applied to the field of reprofiling to help find new drugs from old.

As R&D budgets are cut and blockbusters come off patent, drug discovery is becoming more conservative.  Many companies are taking existing drugs or drug-like compounds as the starting point for the discovery of new chemical entities (NCEs) because they know that this is the most likely root to success.  In my last post I discussed Using Pharmacophores to Find New Targets for Existing Drugs.  This month I’m taking a look at the technique of scaffold hopping that makes changes to existing drugs.

Scaffold hopping involves a computational search of the chemical space around existing compounds by making structural changes to known drugs.  The aim is to find a new compound that not only retains the activity of the parent compound, but also shows some improvement, either in terms of improved activity or a reduction of side effects.  The fact that the resulting compound will have a similar chemistry to a known active significantly increases the likelihood of activity and, therefore, return on R&D spend.

This approach is well validated.  Bayer’s Levitra was created by altering Pfizer’s Viagra molecule.  The small chemical change involved a substitution of the nitrogen positions in a fused ring, which was not covered by Pfizer’s patent.  Computational analysis of the field patterns of the two compounds shows that this structural change had only a subtle effect on the molecule’s field pattern: computational analysis shows that Levitra and Viagra share a very similar pharmacophore template.

Scaffold hopping using Spark is an ideal approach to finding NCEs from existing compounds.  Spark uses Cresset’s field technology to find biologically equivalent replacements for key moieties.  The activity profile of the new compound is compared to the starting point or to a pharmacophore.  It is an extremely effective method of exploring new chemical space.  Our recent poster: Rapid Technique for New Scaffold Generation highlights the power of scaffold hopping to both explore new chemical space and to provide enhanced protection for NCEs.

Viagra Levitra Unknown

Above left: Sildenafil (Viagra) from pdb code 1udt; Above center: Vardenafil (Levitra) found by scaffold hopping in Spark; Above right: Potential PDE5 active that mimics both Sildenafil and Vardenafil but lies outside of both patent landscapes.

When I left a trial copy of Spark with a customer at a major pharma company he used it to run a scaffold hopping experiment on some of his current leads.  The results blew him away.  Yes,Spark returned some bioisosteres that he had been expecting and had already thought of.  It also returned some that weren’t viable for patent or ADME reasons.  But it also came up with some gold – new, bioisosteric structures that he had not thought of, that were completely ‘out of the box’.  Needless to say, he bought the software.

In the next post I’ll talk about a recent collaboration between Cresset and RedX that focuses on discovering NCEs by switching the oxidation state of known drugs.

Previous posts in this series:

Dr Robert Scoffin,