The world outside drug-like chemical space

Where do the new opportunities lie?

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Volatile and competitive fields, such as drug discovery, can tend to closely adhere to trends, as all players are keen to be on the cutting edge and not be left behind. In their editorial “Horses for courses: reaching outside drug-like chemical space for inhibitors of challenging drug targets” in the latest edition of Future Medicinal Chemistry, Adrian Whitty and Li Zhou closely examine ‘druglikeness’ guidelines and look for the next step in drug discovery.

The new direction being taken in target identification away from neat binding sites towards whole new classes such as: protein-protein interactions and DNA, carbohydrate or phosphopeptide binding. Additionally many challenging targets would be considered un-druggable if the traditional druglike criteria were rigidly stuck to.

Whitty and Zhou choose four categories where reaching beyond typical measures of druglikeness are less useful. The categories they identify are: natural product-inspired (NP) chemotypes, macrocycles and cyclic peptides, peptide foldamers and covalent inhibitors. In each case Whitty and Zhou outline the challenges of including each class (or subclasses of them) in the drug discovery process and what might be done to more easily integrate them.

In the case of NPs, for example, they highlight the fact that the chemical space for NPs and NP-like compounds is unfathomably, impractically large and the majority are unlikely to be pharmacologically interesting. A deeper understanding for what subtypes of NP would interact with the targets of interest with favorable ADME properties is a daunting necessity. Despite these problems; they note that of the 24 NPs which led to approved drugs, half of them would not pass strict measures of druglikeness.

Outside of the comfortable world of druglikeness there is obviously fertile ground for future drugs, if we can find better ways to reap them.

Read the whole freely available editorial here

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Gerald PJ Clarke

Contributor, FSG

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