The Rule of Five revisited: applying log D in place of log P in drug-likeness filters.
The much publicized "Rule of 5" has been widely adopted among the pharmaceutical industry. It is used as a first step filter to perform virtual screening of compound libraries, in an effort to quickly eliminate lead candidates that have poor physicochemical properties for oral bioavailabilty. One of the key parameters used therein is log P, which is a useful descriptor, but one that fails to take into account variation in the lipophilicity of a drug with respect to the ionic states present at key biological pH values. Given that the majority of commercial pharmaceuticals contain an ionizable moiety, we propose that log D is a better descriptor for lipophilicity in the context of the Rule of 5. It gives more physiologically relevant results, thereby reducing the number of potential false-negatives incorrectly eliminated in screening. Using a series of commercial compound libraries, this study showed that the adapted Rule of 5 using log D instead of log P provides notable improvement in pass rate for compounds that have the desired lipophilicity at a relevant physiological pH.
Bhal
Sanjivanjit K
SK
Advanced Chemistry Development, Inc. (ACD/Labs), 110 Yonge Street, 14th Floor, Toronto, ON, Canada, M5C 1T4.
Kassam
Karim
K
Peirson
Ian G
IG
Pearl
Greg M
GM
D000284:Administration, Oral; D001682:Biological Availability; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D019295:Computational Biology; D015195:Drug Design; D007477:Ions / Q000737:chemistry; D008055:Lipids / Q000737:chemistry; D008954:Models, Biological; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000145:classification / Q000378:metabolism; D012985:Software Design; D012995:Solubility; D013329:Structure-Activity Relationship
D007477:Ions; D008055:Lipids; D004364:Pharmaceutical Preparations