See how thermodynamics can be used to improve your lead optimization process. Renin is an aspartyl protease involved in the production of angiotensin II, a potent vasoconstrictor. Renin inhibitors can prevent blood vessel constriction and could therefore be useful for the treatment of hypertension. High throughput screening efforts identified a small molecule renin inhibitor with a core substituted diaminopyrimidine ring. Parallel medicinal chemistry efforts based on this lead resulted in compound 1. A complex of 1 bound to renin was crystallized and structural data obtained by X-ray diffraction. The structure indicated there were adjacent unoccupied binding pockets. Synthetic efforts were initiated to extend functionality into these pockets to improve affinity and adjust pharmacokinetic parameters.

Thermodynamics data for inhibitor binding to renin were also collected using isothermal titration calorimetry. These data were used to help guide inhibitor optimization by suggesting molecular alterations to improve binding affinity from both a thermodynamic and structural perspective. Addition of a methoxy-propyl group extending into the S3 subpocket improved inhibitor affinity and resulted in greater binding enthalpy. Initial additions to the pyrimidine ring template that extended into the large hydrophobic S2 pocket did not improve affinity and dramatically altered the thermodynamic driving force for the binding interaction. Binding of the core template was enthalpically driven whereas binding of initial inhibitors with S2 extensions were both enthalpically and entropically driven but lost significant binding enthalpy. Additional electrostatic interactions were then incorporated in the S2 extension to improve binding enthalpy while taking advantage of the favorable entropy.

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