Kinase chemogenomics: targeting the human kinome for target validation and drug discovery.

Chemogenomics is a gene family-based approach to drug discovery and target validation. This review will summarize the application of this interdisciplinary approach to the protein kinases of the human genome with emphasis upon the synergies and efficiencies to be gained. Specific examples from the SAPK-family will be discussed.

Estimation of binding affinities for selective thrombin inhibitors via Monte Carlo simulations.

Monte Carlo simulations have been performed on a series of 20 active-site-directed thrombin inhibitors to determine the interactions and energetics associated with the binding of these compounds. Physicochemical descriptors of potential value in the prediction of binding affinities were averaged during simulations of each inhibitor unbound in water and bound to thrombin. Regression equations based on 3-5 descriptors are able to reproduce the experimental binding affinities, which cover a 7 kcal/mol range, with rms errors of 1.0-1.3 kcal/mol, and yield correlation coefficients, r(2), of 0.7-0.8. On the basis of these results, the quantities most important in determining the binding affinities are: (1) the enhancement of van der Waals interactions in going from solution to the bound state, (2) the intramolecular strain induced in the inhibitor upon binding, (3) the number of hydrogen bonds lost in the binding process, and (4) the number of rotatable bonds in the inhibitor. The descriptors are physically reasonable and, in combination with the insights gained from analysis of the simulation structures, suggest directions for the development of improved thrombin inhibitors.

Differential growth hormone responses to glucose and growth hormone releasing hormone in lactating dairy cows.

Dairy cows in early lactation were reported to secrete growth hormone in response to declining glucose concentrations at day 5 but not day 30 post-partum, whereas GH responses to TRH were reported to be enhanced after day 30 post partum. The present study examined GH response following glucose infusion and the effect of GHRH as well as effects of SRIH on GHRH-stimulated GH release. Declining plasma glucose concentrations after glucose infusion stimulated GH release at day 5 post partum but not in nonpregnant, nonlactating cows or in cows at days 30 and 90 post partum. GHRH stimulated GH release on all days tested, but the response was highest at day 30 post partum when compared to other days. Somatostatin infusion inhibited GHRH effects on GH concentrations only at day 30 post partum and in nonpregnant, nonlactating cows. Thus, a differential response of the GH regulatory system could be demonstrated between days 5 and 30 post partum utilizing different stimuli. Evaluation of plasma glucose and free fatty acid concentrations on days 5, 10, 20, and 30 post partum revealed a progressive decrease in FFA but not glucose as lactation progressed. Decreased plasma FFA concentrations were paralleled by a decrease in basal GH, somatomedin-C and epinephrine. Thus, a decline in FFA may be responsible for the disparity between effects of GHRH and glucose on GH release between days 5 and 30 post partum.