Oral druggable space beyond the rule of 5: insights from drugs and clinical candidates

Chem Biol. 2014 Sep 18;21(9):1115-42. doi: 10.1016/j.chembiol.2014.08.013.


The rule of 5 (Ro5) is a set of in silico guidelines applied to drug discovery to prioritize compounds with an increased likelihood of high oral absorption. It has been influential in reducing attrition due to poor pharmacokinetics over the last 15 years. However, strict reliance on the Ro5 may have resulted in lost opportunities, particularly for difficult targets. To identify opportunities for oral drug discovery beyond the Ro5 (bRo5), we have comprehensively analyzed drugs and clinical candidates with molecular weight (MW) > 500 Da. We conclude that oral drugs are found far bRo5 and properties such as intramolecular hydrogen bonding, macrocyclization, dosage, and formulations can be used to improve bRo5 bioavailability. Natural products and structure-based design, often from peptidic leads, are key sources for oral bRo5 drugs. These insights should help guide the design of oral drugs in bRo5 space, which is of particular interest for difficult targets.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Administration, Oral
  • Biological Products / chemistry
  • Biological Products / metabolism
  • Databases, Factual
  • Drug Delivery Systems
  • Drug Discovery*
  • Humans
  • Macrocyclic Compounds / chemistry
  • Macrocyclic Compounds / metabolism
  • Molecular Weight
  • Pharmaceutical Preparations / chemistry*
  • Pharmaceutical Preparations / metabolism
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / metabolism


  • Biological Products
  • Macrocyclic Compounds
  • Pharmaceutical Preparations
  • Protease Inhibitors