Specific molecular structure indicates if a drug is likely to be safe for clinical use

6 October 2014

A test developed at the University of Manchester helps determine which  drugs are unlikely to work because of their molecular structure. This is likely to greatly speed up the time it takes to make safe and effective medicines available and reduce costs of drug discovery. The findings are published online in the journal Metabolomics.

In 2013, researchers at The University of Manchester helped create a ground-breaking computer model that replicates how the human metabolic network works. A kind of ‘instruction manual’ for how our metabolism interacts with human diseases, this model means scientists now know most of the small molecules that are used by our bodies as part of our normal biochemistry.

Armed with this knowledge, the University’s research team, led by Professor Douglas Kell of its School of Chemistry and the Manchester Institute of Biotechnology, compared the structures of all these molecules, known as metabolites, with all marketed drugs (including natural products). They also compared drugs and metabolites with synthetic chemicals from a commercial Maybridge chemical library.

Professor Kell said, “We immediately saw a very strong correlation. More than 90% of marketed drugs — and we tested over 1300 of the FDA’s (Food and Drug Administration) approved drugs — bear a structural similarity of at least 0.5 to at least one metabolite. In other words, they look very like them. This new ‘rule of 0.5’ does not mean that a molecule obeying it will necessarily become a successful drug, but what it does mean is that we can now say that a molecule that does not obey it, is very unlikely to succeed.”

A famous test, colloquially called the ‘rule of 5’, was developed by Chris Lipinski and colleagues from Pfizer in 1997. The rule sets down four properties that a synthetic molecule should obey if it is to have a chance of becoming a successful drug. However, the rule doesn’t normally work for naturally-occurring products, that is, drugs with active ingredients that come from nature (penicillin, for example, which is produced by Penicillium fungi). Nearly half of new drugs are based on naturally-occurring substances.

This new finding should be of considerable value in avoiding the costly problems of attrition, freeing up more resources for developing effective medicines and making them available more quickly for those who need them.


O'Hagan, N. Swainston, J. Handl, & D. B. Kell (2014). A 'rule of 0.5' for the metabolite-likeness of approved pharmaceutical drugs.  Metabolomics.

More information

More information about the computer model that replicates the human metabolic network:


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