Binding thermodynamics of substituted diaminopyrimidine renin inhibitors.

Renin is an aspartyl protease involved in the production of angiotensin II, a potent vasoconstrictor. Renin inhibitors can prevent blood vessel constriction and therefore could 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 were obtained by X-ray diffraction. The structure indicated that there were adjacent unoccupied binding pockets. Synthetic efforts were initiated to extend functionality into these pockets so as 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 thermodynamic and structural perspectives. The addition of a methoxypropyl 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 was both enthalpically and entropically driven but lost significant binding enthalpy. Additional electrostatic interactions were then incorporated into the S2 extension to improve binding enthalpy while taking advantage of the favorable entropy.

No more Hiroshimas.

KIE: Dyer reports on the ninth World Congress of International Physicians for the Prevention of Nuclear War (IPPNW), held in Hiroshima, Japan, in October 1989. Taking as their theme "No more Hiroshimas," IPPNW participants visited the sites of the only acts of nuclear war -- the 1945 U.S. bombings of Hiroshima and Nagasaki that ended World War II. Scientific sessions updated information on the health effects of radiation. The congress issued an appeal for "a new agenda of moral priorities" that urges the implementation of five measures: the immediate cessation of all nuclear testing; a halt to the production of bomb-grade fissile material; conversion of secret weapons laboratories to open scientific institutes addressing environmental issues; reallocation of 50% of military spending to health and environmental projects; and the establishment of a U.N. Peace Research Centre at Hiroshima and a scholarship program to educate future world leaders about nuclear war.^ieng