Today’s drug discovery and the shadow of the rule of 5

ABSTRACT

Introduction

The rule of 5 developed by Lipinski et al., a landmark and prescient piece of scholarship, focused the minds of drug hunters by systematically characterizing the physical make-up of drug molecules for the first time, noting many sub-optimal compounds identified by high-throughput screening practices. Its profound influence on thinking and practices, whilst providing benefit, perhaps etched the guidelines too strongly in the minds of some drug hunters who applied the bounds too literally without understanding the implications of the underlying statistics.

Areas covered

This opinion is based on recent key developments that take thinking, measurements, and standards beyond those first set out, particularly the influences of molecular weight and the understanding, measurement, and calculation of lipophilicity.

Expert opinion

Techniques and technologies for physicochemical estimations set new standards. It is timely to celebrate the significance and influence of the rule of 5, whilst taking thinking to new levels with better characterizations. The shadow of the rule of 5 may be long, but it is not dark, as new measurements, predictions and principles emerge as guiding lights in the design and prioritization of higher-quality molecules redefining the meaning of beyond the rule of 5.

KEYWORDS:

• Drug discovery
• physicochemical properties
• rule of 5
• lipophilicity
• solubility
• permeability
• drug transporters

Article highlights

• A contemporary appraisal on the seminal ‘Rule of 5’ suggests moving on from the thinking employed is long overdue; much more changed over 25 years.

• Advances in understanding, measurement, and prediction of lipophilicity fundamentally change expectations.

• Molecular weight, the most frequently broken element of the rule, should not be a constraint and is probably irrelevant.

• Observations with measured solubility, permeability, and pharmacokinetic data illustrate that one ‘rule’ cannot cover all.

• Optimization of lipophilicity is imperative for permeation, but role of membrane transporters has profound implications.

Declaration of interest

Robert Young is a former employee and pensioner of GlaxoSmithKline and is a member of the SpiroChem Scientific Advisory Board. He is also a consultant with Blue Burgundy (Drug Discovery Consultancy) Ltd. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript is not funded.