Biophysical methods in early drug discovery.

Geoffrey Holdgate,Kevin Embrey,Gareth Davies,Alexander Milbradt

doi:10.5599/admet.733

Abstract

Biophysical methods such as mass spectrometry, surface plasmon resonance, nuclear magnetic resonance, and both differential scanning isothermal titration calorimetry are now well established as key components of the early drug discovery process. These approaches are used successfully for a range of activities, including assay development, primary screening, hit confirmation and detailed mechanistic characterisation of compound binding. Matching the speed, sensitivity and information content of the various techniques to the generation of critical data and information required at each phase of the drug discovery process has been key. This review describes the framework by which these methods have been applied in the drug discovery process and provides case studies to exemplify the impact.

Highlights

Biophysical methods, which can encompass a wide range of techniques focussed on measuring the structure, properties, dynamics or function of biomolecules, have been increasingly employed in the drug discovery process since their first introduction in the early 1990s
Existing biophysical approaches were used in novel ways to identify and characterise protein-ligand interactions, for example the first report of the use of affinity selection, coupled to detection by mass spectrometry, for the identification of molecules binding to a macromolecule [3], and the use of nuclear magnetic resonance (NMR) to identify fragments that could subsequently be optimised and linked to form more potent compounds [4]
Over the last 5 years or so, this progression has been driven by the impact these methods have had, an increased throughput for some methods, and the recognition that a better understanding of the reagents, tools, assays and that mechanistic characterisation and differentiation of hits yields a more efficient early stage drug discovery process

Summary

Introduction

Biophysical methods, which can encompass a wide range of techniques focussed on measuring the structure, properties, dynamics or function of biomolecules, have been increasingly employed in the drug discovery process since their first introduction in the early 1990s. Existing biophysical approaches were used in novel ways to identify and characterise protein-ligand interactions, for example the first report of the use of affinity selection, coupled to detection by mass spectrometry, for the identification of molecules binding to a macromolecule [3], and the use of nuclear magnetic resonance (NMR) to identify fragments that could subsequently be optimised and linked to form more potent compounds [4] The development of these biophysical methods coincided with the advent of high-throughput screening (HTS), leading from natural product screening of a few hundred compounds each week in the late 1980s, through to HTS hits being responsible for starting matter for almost half of drug companies’ portfolios in the mid-1990s [5,6]. Methods (biochemical and Example information required for acceptable biophysical) quality control

Functionality

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Discussion

Conclusions