Going further than Lipinski's rule in drug design

Introduction: Lipinski's 1997 publication of the ‘Rule of 5’ (Ro5) was one of the most influential recent medicinal chemistry publications. In the almost 15 years since the publication of the original Ro5 paper, multiple groups have refined and expanded on the Ro5 and proposed additional heuristics to guide medicinal chemistry programs. While many variations on the Ro5 have been proposed, the majority of these remain close to the original guidelines proposed by Lipinski et al. Areas covered: This review provides an overview of heuristic methods for the design of drug-like molecules. The article also provides the reader with suggestions on future directions for the field. Expert opinion: While Lipinski's publication of the Ro5 and subsequent work by other authors has made medicinal chemists more aware of the relationships between physical properties and ADMET, it has hardly been a panacea. Pharmaceutical productivity continues to lag, and the industry is exploring new models to improve its output. If we are to progress, we need to move beyond simple models based on lipophilicity and gain a deeper understanding of molecular interactions.