The Rule of Five Revisited: Applying Log <i>D</i> in Place of Log <i>P</i> 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. Keywords: Rule of 5; log P; log D; partition coefficient; distribution coefficient; lipophilicity; drug-likeness; physicochemical property prediction; property profiling; library screening; oral bioavailability; permeabilit

The Rule of Five Revisited: Applying Log <i>D</i> in Place of Log <i>P</i> 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. Keywords: Rule of 5; log P; log D; partition coefficient; distribution coefficient; lipophilicity; drug-likeness; physicochemical property prediction; property profiling; library screening; oral bioavailability; permeabilit

A Hand-held Fiber-optic Implement for the Site-specific Delivery of Photosensitizer and Singlet Oxygen

We have constructed a fiber optic device that internally flows triplet oxygen and externally produces singlet oxygen, causing a reaction at the (Z)-1,2-dialkoxyethene spacer group, freeing a pheophorbide sensitizer upon the fragmentation of a reactive dioxetane intermediate. The device can be operated and sensitizer photorelease observed using absorption and fluorescence spectroscopy. We demonstrate the preference of sensitizer photorelease when the probe tip is in contact with octanol or lipophilic media. A first-order photocleavage rate constant of 1.13 h−1 was measured in octanol where dye desorption was not accompanied by readsorption. When the probe tip contacts aqueous solution, the photorelease was inefficient because most of the dye adsorbed on the probe tip, even after the covalent ethene spacer bonds have been broken. The observed stability of the free sensitizer in lipophilic media is reasonable even though it is a pyropheophorbide-a derivative that carries a p-formylbenzylic alcohol substituent at the carboxylic acid group. In octanol or lipid systems, we found that the dye was not susceptible to hydrolysis to pyropheophorbide-a, otherwise a pH effect was observed in a binary methanol-water system (9:1) at pH below 2 or above 8