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.

Sir James Black, winner of the 1988 Nobel Prize in Physiology and Medicine, famously stated that “The most fruitful basis for the discovery of a new drug is to start with an old drug”. Disillusioned with HTS, and struggling to bring new chemical entities to market, many companies are turning back to Sir James’ wisdom. They are finding unexploited potential in the chemical space around existing drugs, and this is leading to real therapeutic and business returns.

Re-using existing drugs is the lowest risk approach a company can take to developing their drug portfolio and exploiting their existing intellectual property. At the simplest level, this means reformulation, and of course pharmaceutical companies are continually reformulating. New formulations can lead to better patient convenience by improving the delivery method or by increasing the half-life so that less frequent doses are required.

AstraZeneca developed Nexium by making process changes to the production of their existing drug Omeprazole and selecting only the structure with a single enantiomer. Nexium was the second highest selling pharmaceutical in the US in 2011.

Another straightforward way to re-use an existing drug is to combine it with another drug to find synergies. GlaxoSmithKline’s Advair, with US sales of $4.7 billion in 2010, was the result of combining the two pre-existing asthma treatments Salmeterol and Fluticasone.

The third main way to re-use an existing drug is to repurpose it in a new therapeutic area. Many companies look for alternative indications for their own drugs in order to extend the market and the patent life for a compound. Literature searches can reveal side effects or off label usage of drugs that point to applications against a new target.

For example, Johnson and Johnson’s anticonvulsant drug Topiramate was originally approved by the FDA in 1996 as a treatment for epilepsy. It is now most frequently prescribed as a treatment for migraine, for which it was approved in 2004.

In my next posts I’ll focus on how computational chemistry can help find new drugs by taking an existing drug as the starting point for research. This is variously called reprofiling, repurposing, re-using, or new drugs from old. Sometimes it’s even called patent busting. At the Cresset 2012 EU UGM in Cambridge, UK, Dr Alan Rothaul gave an overview of structure and non-structure based methods of drug repositioning and showed how structure based re-profiling through fragment swapping can feed into new compound discovery.

I’ll explore how Cresset software is helping researchers to take advantage of this profitable approach by:

• Using pharmacophores to find new targets for existing drugs
• Searching nearby chemical space (1) – scaffold hopping
• Searching nearby chemical space (2) – switching oxidation states

Dr Robert Scoffin,
CEO