Multi-pH QSAR: A Method to Differentiate the Activity of Neutral and Ionized Species and Obtain True Correlations when Both Species are Involved

✍ Scribed by Robert A. Scherrer; Albert J. Leo

• Publisher: Wiley (John Wiley & Sons)
• Year: 2010
• Tongue: English
• Weight: 322 KB
• Volume: 29
• Category: Article
• ISSN: 1868-1743
• DOI: 10.1002/minf.201000093

✦ Synopsis

Abstract

Classical Hansch analysis for most series of ionizable compounds cannot identify the active species as being neutral or ionized. The log P^N^ and log P^I^ of these series are too highly correlated. We have found a simple solution to this problem by just combining data obtained at more than one pH (multi‐pH QSAR). A bonus is that the statistical power of a series is increased one fold for each pH level added. Datasets of simple homologous series serve as proofs of concept. Two of these reveal hidden correlations involving both the neutral and ionized species. These “true” correlations would be impossible to find at a single pH. An example is the inhibition of monoamine oxidase by a series of primary n‐alkylamines. Multi‐pH QSAR indicates that the protonated amine enhances inhibition and the neutral species diminishes it. This paper illustrates the first substantial use in QSAR of the species‐specific terms, log D^N^ (neutral) and log D^I^ (ionized). Multi‐pH QSAR can give direction to lead development and facilitate the In‐Silico modeling of ADMET processes by associating rate‐limiting steps with the correct ionization state.