Beyond the Rule of Five

Two decades on from its initial publication, Lipinski’s “rule of five” is arguably one of the most influential concepts in modern drug discovery. Yet it is also one of the most controversial. Developed with the aim of prioritizing the progression of drug candidates with the most promising oral bioavailability properties, Lipinski’s rules have had a lasting effect on drug discovery strategies and the curation of compound screening libraries. They have also inspired the creation of other similar selection criteria, such as GlaxoSmithKline’s 4/400 and Pfizer’s 3/75 rules.

The origins of the rule of five lie in a study of the favorable absorption properties of orally administered drugs and clinical candidates, conducted by Chris Lipinski and colleagues at Pfizer in 1997 (1). For four key physicochemical properties, cut-offs were calculated that covered 90 percent of the molecules studied. In short, molecules with the best solubility and permeability were found to have:

• molecular weights less than 500 Da
• calculated octanol–water coefficients (CLogP) not greater than five
• no more than five hydrogen bond donors
• no more than 10 hydrogen bond acceptors.

All numbers are multiples of five – hence the name “rule of five”. However, what was originally intended as a rule-of-thumb soon became dogma. The pharmaceutical industry can be heavily influenced by precedent – or rather, motivated by a fear of missing out. Somewhere along the way, these guidelines for oral bioavailability became confused with rules for drug likeness, and I find that the industry often prioritizes Lipinski’s rules at all costs.

With attrition still a significant problem for the industry – 2016 saw FDA new drug approvals fall to a six-year low (2) – and the cost of bringing a new medicine to market still eye-wateringly high (as much as $2.6 billion per approval, according to figures published by the Tufts Center for the Study of Drug Development), many people have questioned the value of a rigid interpretation of these rules. For starters, the hard cut-offs used to de-prioritize hits could lead to missed opportunities. Is a drug candidate with a molecular weight of 501 Da really worth losing over a candidate with a similar  structure but a molecular weight of 499 Da? Perhaps... perhaps not.

I believe that drug discovery should be based on measurement rather than theoretical prediction. There are certainly many notable examples of successful drugs that violate at least two of Lipinski’s rules: take the HMG-CoA reductase inhibitor atorvastatin, for example, or leukotriene receptor antagonist montelukast. Rigid interpretation of Lipinski’s rules comes at the expense of chemical diversity. Indeed, some of the biggest challenges in drug discovery require us to think beyond our current design space.

In the urgent search for new and effective antimicrobials, for example, tweaking the structure of existing molecules will not be sufficient – we need to identify entirely new structures. A focus on natural products, the vast majority of which violate Lipinski’s rules, could be one effective solution.

Moreover, genomic approaches to target discovery suggest that we’ve only just scratched the surface as far as modulating biological pathways are concerned. It is becoming increasingly apparent that the vast majority of potential targets cannot be modulated according to the “lock and key” model. To disrupt more challenging targets, such as transcription factors and scaffolding proteins, interfering with protein–protein interactions will be key. Here, larger, more hydrophilic molecules, including macromolecules and natural products, could be more effective than conventional small molecules.

In our search for diversity, it is worth remembering that Lipinski’s rules were developed with oral delivery in mind. For localized treatment of pulmonary targets, for example, these Lipinski-like attributes can actually reduce therapeutic effectiveness. Though the rule of five has helped to further our understanding of the effects of physicochemical properties on oral bioavailability, careful consideration of how and when it is applied is crucial as we start fully exploring the chemical space available to us. Otherwise, we will unnecessarily limit our creativity, which could be harmful to drug discovery.

So, just like Captain Hector Barbossa in Pirates of the Carribean: The Curse of the Black Pearl, we should consider that “the code [rule of five] is more what you’d call ‘guidelines’ than actual rules.”