50 research outputs found
Crystal structure of Bacillus anthracis dihydrofolate reductase with the dihydrophthalazine-based trimethoprim derivative RAB1 provides a structural explanation of potency and selectivity
Bacillus anthracis possesses an innate resistance to the antibiotic trimethoprim due to poor binding to dihydrofolate reductase (DHFR); currently, there are no commercial antibacterials that target this enzyme in B. anthracis. We have previously reported a series of dihydrophthalazine-based trimethoprim derivatives that are inhibitors for this target. In the present work, we have synthesized one compound (RAB1) displaying favorable 50% inhibitory concentration (54 nM) and MIC (</=12.8 ug/ml) values. RAB1 was cocrystallized with the B. anthracis DHFR in the space group P212121, and X-ray diffraction data were collected to a 2.3-A resolution. Binding of RAB1 causes a conformational change of the side chain of Arg58 and Met37 to accommodate the dihydrophthalazine moiety. Unlike the natural substrate or trimethoprim, the dihydrophthalazine group provides a large hydrophobic anchor that embeds within the DHFR active site and accounts for its selective inhibitory activity against B. anthracis.Peer reviewedVeterinary PathobiologyChemistr
Biological, proton-magnetic-resonance- and ultraviolet-spectroscopic evidence for a molecular complex of actinomycin D and 10,11-dihydro-3H-naphth[1,2-g]indazol-7-ol (Short Communication)
SHetA2 interference with mortalin binding to p66shc and p53 identified using drug-conjugated magnetic microspheres
Phosphorino[4,3-d]pyrimidines. III. Synthesis, resolution, and properties of 4-substituted phosphorino[4,3-d]pyrimidines
4,5-Dimethylbenzene-1,2-dimethanol
An efficient and cost-effective synthesis of 4,5-dimethylbenzene-1,2-dimethanol is reported. The synthesis is accomplished in three steps with an overall yield of 80%