April 6–10, 2008, ACS Spring 2008, New Orleans, LA, USA

Giving the Rule-of-5 a More Accurate Twist

Greg Pearl

Abstract

The much publicized "Rule-of-5" (Ro5) has been widely adopted in the pharmaceutical industry as the first step in the virtual screening of compound libraries, to pre-emptively eliminate hits that are deemed to have poor physicochemical properties for oral bioavailability; and in lead optimization to filter out less suitable compounds.

LogP is a key parameter in the Ro5 and one that is inordinately familiar to medicinal chemists. Although it is useful, it fails to take into account variation in drug lipophilicity due to ionization under physiological conditions. Given that more than 95% of commercial pharmaceuticals contain an ionizable moiety, we propose that logD is a better descriptor for lipophilicity in the Ro5 (and similar filters).

In this presentation we will discuss the important differences between logP and logD, and results from screening a number of commercially-available libraries using an adapted Ro5 applying logD in place of logP.

Download the presentation in Adobe Acrobat format (702 Kb PDF file).

Relevant Products: ACD/LogD, ACD/LogP DB

Relevant Solution: Physicochemical Property Prediction and Property-Based Design