High-throughput pK_a screening and prediction amenable for ADME profiling

Abstract

Recent technological advances have made it possible for several new pK_a assays to be used in drug screening. In this review, a critical overview is provided of current new methodologies for high-throughput screening and prediction of pK_a. Typical applications of using pK_a constants and charge state for absorption, distribution, metabolism and excretion (ADME) profiling and quantitative structureactivity relationship modelling complements the methodological comparisons and discussions. The experimental methods discussed include high-throughput screening of pK_a by multiplexed capillary with ultraviolet absorbance detection on a 96-capillary format instrument, capillary electrophoresis and mass spectrometry (CEMS) based on sample pooling, determination of pK_a by pH gradient high-performance liquid chromatography, and measurement of pK_a by a mixed-buffer liner pH gradient system. Comparisons of the different experimental assays are made with emphasis on the newly developed CEMS method. The current status and recent progress in computational approaches to pK_a prediction are also discussed. In particular, the accuracy limits of simple fragment-based approaches as well as quantum mechanical methods are addressed. Examples of pK_a prediction from in-house drug candidates as well as commercially available drug molecules are shown and an outline is provided for how drug discovery companies can integrate experiments with computational approaches for increased applications for ADME profiling.

Keywords::

• ADME
• capillary electrophoresis
• high-throughput screening
• ionisation
• pK_a
• prediction

Acknowledgement

RA Thompson is greatly acknowledged for reviewing the manuscript and for valuable comments.