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Drug discovery beyond the rule of 5 - Opportunities and challenges

Targets that are ‘difficult-to-drug’ typically have binding sites that are large, highly lipophilic or polar, flexible, flat or featureless [1]. They contain few opportunities for high affinity interaction with drugs that comply with Lipinski’s rule of 5 [2] (Ro5) and are currently modulated with biologicals such as native proteins or antibodies. However, with few exceptions, biologicals lack cell permeability and can therefore not be used for intracellular targets nor can they be delivered orally. Unfortunately, many novel, potential drug targets identified through the rapid advances in genomics and proteomics are intracellular and may well be ‘difficult-to-drug’ with Ro5 compliant ligands, just as some established target classes. Development of approaches for modulation of difficult targets is therefore a key priority in efforts to deliver innovative medicines and to improve the efficacy of drug discovery.