The Rule of Five Revisited:  Applying Log D in Place of Log P in Drug-Likeness Filters

Abstract

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.

Effect of Drug Lipophilicity and Ionization on Permeability Across the Buccal Mucosa: A Technical Note

“…However, logP does not encompass the extent of ionization of ionizable molecules. As 95% of all drugs have ionizable groups, distribution coefficient (logD) that considers the extent of ionization as well as intrinsic lipophilicity may be a better descriptor that reflects the partitioning of a mixture of drug species as well as the actual drug lipophilicty at any given pH (7).…”

Modifications of the chemical structure of phenolics differentially affect physiological activities in pulvinar cells of Mimosa pudica L. II. Influence of various molecular properties in relation to membrane transport

“…The rule states that an orally active drug has no more than one violation of the following criteria: (i) no more than five hydrogen bond donors, (ii) no more than ten hydrogen bond acceptors, (iii) a molecular mass less than 500 Da, and, finally, (iv) an octanol-water partition coefficient logP not greater than 5 (Lipinski et al 1997). This rule has been subsequently completed or amended by many authors to try to improve prediction models (Bergstrom et al 2014, Bhal et al 2007, Deconinck et al 2007, Gozalbes et al 2011, Kim et al 2014, Kujawski et al 2012, Palm et al 1997, Talevi et al 2011, van de Waterbeemd et al 2003, Veber et al 2002, Winiwarter et al 2003, Winiwarter et al 1998. To our knowledge, this approach was never or rarely developed in plant physiology to evaluate the capacity of a chemical to passively cross the plasma membrane.…”

Identification of novel drug candidate against Mycobacterium Tuberculosis InhA protein through Computer aided drug discovery

“…28 The 3D structures saved in PDB format has submitted to the drugfiltering tool at http://www,scfbio-iitd.res.in/utility/ LipinskiFilters.jsp.…”