Thursday, December 5, 2013
Box 1. Rules of engagement.
Chris Lipinski and colleagues at Pfizer Inc. defined the 'rule
of five' after analyzing the physicochemical properties of over 2,000 drugs.1
They proposed that compounds would be more likely to be orally available if
they had: (1) molecular weight lower than 500 Da, (2) hydrophobicity measure
log P less than 5,
(3) fewer than 5 hydrogen bond donors and (4) fewer than 10 hydrogen bond
acceptors. All the numbers in the four listed criteria are multiples of five-hence
the name 'rule of five'.
of five remains a topic of debate among medicinal chemists who employ it
broadly but continue to discuss its pros and cons.2
SciBX addressed this
in the conversation with Lipinski.
SciBX: What are the main limitations of using
the rule of five in drug discovery?
Chris Lipinski: The problem with the rule of five and
with other rules is that they can be misused. The rule of five is a rule with
hard cutoffs: log P greater than 5 is bad; log P less than 5 is
good. To say a compound with log P of 4.99 is acceptable and with log P
[of] 5.01 isn't makes no sense whatsoever, so you need to use common sense.
If your strategy is to screen out anything with a log P greater than 3 and a molecular weight greater than 400
you'll discover many GPCR ligands, phosphodiesterase targets and some kinases,
but you will miss just about every possible protein-protein interaction target
and you'll have a lot of trouble with peptidergic GPCRs and protease targets.
So by being too limiting on the rules you eliminate great swaths of
target space that you'd really like to interrogate.