Current perspectives in fragment based lead discovery (FBLD)

It is over 20 years since the first fragment-based discovery projects were disclosed. The methods are now mature for most ‘conventional’ targets in drug discovery such as enzymes (kinases and proteases) but there has also been growing success on more challenging targets, such as disruption of protein–protein interactions. The main application is to identify tractable chemical startpoints that non-covalently modulate the activity of a biological molecule. In this essay, we overview current practice in the methods and discuss how they have had an impact in lead discovery – generating a large number of fragment-derived compounds that are in clinical trials and two medicines treating patients. In addition, we discuss some of the more recent applications of the methods in chemical biology – providing chemical tools to investigate biological molecules, mechanisms and systems

Genetic divergence in mitochondrial DNA of Anopheles nuneztovari (Diptera: Culicidae) from Brazil and Colombia

In the present study, we have examined the variability in Anopheles nuneztovari mitochondrial DNA of three populations from the Brazilian Amazon and one from western Colombia (Sitronela), using four restriction endonucleases (BclI, ClaI, HindIII, SstI). The haplotype diversity (h) was slightly elevated in all populations (0.5000 to 0.6765), whereas the nucleotide diversity (π) was lower in the Sitronela population (0.0029) and higher in populations from the Brazilian Amazon (0.0056 to 0.0098). The degree of sequence divergence (δ) estimated within the Brazilian Amazon and that in Sitronela (0.0329 to 0.0371) suggests that these geographic populations of A. nuneztovari may eventually constitute separate species. The low sequence divergence values among the three Brazilian Amazon populations (0.0012 to 0.0031) indicate that these populations are genetically similar. These results are consistent with those recently reported for allozymes of these same populations

The effect of feeding alfalfa straw sprayed with a curing agent to heifer calves.

Ten good quality Hereford heifer calves were divided into two lots of five calves each fur use in this test. They were the lightest heifers of 80 head purchased from the Brite Ranch at Marfa, Texas. They were fed prairie hay and 1 pound of soybean pellets per head daily until started on test December 22, 1952. The alfalfa straw used in the test was obtained in the vicinity of the college. The sprayed straw came from Dr. N. D. Harwood and was produced on a farm a few miles west of Manhattan, Kansas. It was stemmy but had a good green color. The non-sprayed straw was obtained from Mr. Floyd Cederberg's farm a few miles south of Manhattan, Kansas. It was not as stemmy or as green in color as the Harwood straw. It appeared to have more leaves. The two straws were not comparable in some respects but it was not possible to find more suitable straw, sprayed and non-sprayed. Other data, such as effect of the chemical on the alimentary tract, various organs, tissue, and the extent of its presence in the animal body, will be collected when the animals are slaughtered

Metformin and statin use associate with plasma protein N-glycosylation in people with type 2 diabetes

INTRODUCTION: Recent studies revealed N-glycosylation signatures of type 2 diabetes, inflammation and cardiovascular risk factors. Most people with diabetes use medication to reduce cardiovascular risk. The association of these medications with the plasma N-glycome is largely unknown. We investigated the associations of metformin, statin, ACE inhibitor/angiotensin II receptor blocker (ARB), sulfonylurea (SU) derivatives and insulin use with the total plasma N-glycome in type 2 diabetes. RESEARCH DESIGN AND METHODS: After enzymatic release from glycoproteins, N-glycans were measured by matrix-assisted laser desorption/ionization mass spectrometry in the DiaGene (n=1815) and Hoorn Diabetes Care System (n=1518) cohorts. Multiple linear regression was used to investigate associations with medication, adjusted for clinical characteristics. Results were meta-analyzed and corrected for multiple comparisons. RESULTS: Metformin and statins were associated with decreased fucosylation and increased galactosylation and sialylation in glycans unrelated to immunoglobulin G. Bisection was increased within diantennary fucosylated non-sialylated glycans, but decreased within diantennary fucosylated sialylated glycans. Only few glycans were associated with ACE inhibitor/ARBs, while none associated with insulin and SU derivative use. CONCLUSIONS: We conclude that metformin and statins associate with a total plasma N-glycome signature in type 2 diabetes. Further studies are needed to determine the causality of these relations, and future N-glycomic research should consider medication a potential confounder