Bhal Sanjivanjit K, Kassam Karim, Peirson Ian G, Pearl Greg M
Advanced Chemistry Development, Inc. (ACD/Labs), 110 Yonge Street, 14th Floor, Toronto, ON, Canada, M5C 1T4.
Mol Pharm. 2007 Jul-Aug;4(4):556-60. doi: 10.1021/mp0700209. Epub 2007 May 26.
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.
备受关注的“五规则”已在制药行业中广泛采用。它被用作第一步筛选器，对化合物库进行虚拟筛选，以快速排除那些口服生物利用度的物理化学性质较差的潜在候选药物。其中使用的关键参数之一是log P，它是一个有用的描述符，但未能考虑到药物在关键生理pH值下存在的离子状态的亲脂性变化。鉴于大多数商业药物都含有可电离部分，我们提出log D在“五规则”的背景下是亲脂性的更好描述符。它能给出更符合生理的结果，从而减少筛选中错误排除的潜在假阴性数量。使用一系列商业化合物库，本研究表明，采用log D而非log P的改进版“五规则”，对于在相关生理pH下具有所需亲脂性的化合物，通过率有显著提高。
