Thermodynamics Guided Lead Discovery and Optimization



July 21, 2011

The documented unfavorable changes of physicochemical properties during lead discovery and optimization prompted us to investigate the present practice of medicinal chemistry optimization from a thermodynamic point of view. Basic principles of binding thermodynamics suggest that discriminating enthalpy driven and entropy driven optimizations could be beneficial. We hypothesize that entropy driven optimizations might be responsible for the undesirable trend observed in physicochemical properties. Analyzing the binding thermodynamics of more than 800 protein-ligand complexes we found as a tendency that ligand size increase is accompanied by a decreasing enthalpy component. Due to the opposite slopes of the maximal affinity and the corresponding enthalpy vs. size these lines have an intersection between 20 and 30 heavy atoms that is the typical size of lead compounds. We concluded that the chance of enthalpy driven affinity optimization for larger compounds diminishes rapidly. Consequently we suggest that the characterization of binding thermodynamics is preferred at the lead generation phase. Monitoring binding thermodynamics during optimization programs initiated from thermodynamically characterized hits or leads could improve the physicochemical profile of compounds and therefore the success of discovery programs. In this presentation we show how the assessment of binding thermodynamics could support medicinal chemistry efforts.

Analytical TechniquesChemistryDrug DiscoveryFlow Chemistry

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