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Thermodynamics and kinetics driving quality in drug discovery

31 August 2011  •  Author(s): Geoff Holdgate, AstraZeneca

Recently, there has been renewed interest in using thermodynamic and kinetic data, alongside empirical rules (particularly focused upon cLogP and molecular weight) and guiding metrics such as ligand efficiency and lipophilic ligand efficiency developed for fragments, leads and drugs in order to facilitate the design of compounds with a greater chance of producing successful drugs1. This interest has been assisted both by improvements in instrumentation as well as evidence that thermodynamically and kinetically optimised compounds fare better in the clinic2.

Optimisation of the binding affinity, which may have to be improved by several orders of magnitude from initial hit to drug molecule, can be achieved by modifying the individual thermodynamic and kinetic contributions. However, medicinal chemists have, up to now, been reluctant to consider these measurements during hit selection and lead optimisation, because it has been difficult to understand how the different design strategies affect the individual forces resulting in different thermodynamic and kinetic profiles. By incorporating both retrospective analysis and real time data collection in active projects, the value of using these fundamental contributions to guide the selection of chemical start points and how they can be used to influence optimisation strategies will become clear.

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