Abstract
Coined in 1997, by Christopher Lipinki et al., the rule of five (Ro5) comprises a set of parameters that determine drug-likeness for oral delivery. The parameters are as follows: no more than five hydrogen bond donors (nitrogen or oxygen atoms with one or more hydrogen atoms); no more than ten hydrogen bond acceptors (nitrogen or oxygen atoms); a molecular mass less than 500 Da; and an octanol–water partition coefficient log P no greater than 5. Future Medicinal Chemistry invited a selection of leading researchers to express their views on Lipinski’s Ro5, which has influenced drug design for over a decade. Their enlightening responses provide an insight into the current and future role of Ro5, and other rules of thumb, in the evolving world of medicinal chemistry.
References
- 1 Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev.23(1–3),3–25 (1997).
- 2 Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev.46(1–3),3–26 (2001).
- 3 Jarvis L. Originator of ‘the rule of five’ reflects on 10 years of drug development under its influence. Chem. Eng. News85(45),18 (2007).
- 4 Lipkus AH, Yuan Q, Lucas KA et al. Structural diversity of organic chemistry. a scaffold analysis of the CAS registry. J. Org. Chem.73(12),4443–4451 (2008).
- 5 Zhang MQ, Wilkinson B. Drug discovery beyond the ‘rule-of-five’. Curr. Opin. Biotechnol.18(6),478–488 (2007).
- 6 Davis BA, Erlanson DA. Learning from our mistakes: the ‘unknown knowns’ in fragment screening. Bioorg. Med. Chem. Lett. doi:10.1016/j.bmcl.2013.03.028 (2013) (Epub ahead of print).
- 7 Köster H, Craan T, Brass S et al. A small nonrule of 3 compatible fragment library provides high hit rate of endothiapepsin crystal structures with various fragment chemotypes. J. Med. Chem.54(22),7784–7796 (2011).
- 8 Congreve M, Carr R, Murray C, Jhoti H. A ‘rule of three’ for fragment-based lead discovery? Drug Discov. Today8(19),876–877 (2003).
- 9 Bickerton GR, Paolini GV, Besnard J, Muresan S, Hopkins AL. Quantifying the chemical beauty of drugs. Nat. Chem.4(2),90–98 (2012).
- 10 Segall MD. Multi-parameter optimization: identifying high quality compounds with a balance of properties. Curr. Pharm. Des.18(9),1292–1310 (2012).
- 11 Abad-Zapatero C. A Sorcerer’s apprentice and the rule of five: from rule-of-thumb to commandment and beyond. Drug Discov. Today12(23–24),995–997 (2007).
