10 research outputs found
Chromosomal organization of biosynthetic gene clusters, including those of nine novel species, suggests plasticity of myxobacterial specialized metabolism
IntroductionNatural products discovered from bacteria provide critically needed therapeutic leads for drug discovery, and myxobacteria are an established source for metabolites with unique chemical scaffolds and biological activities. Myxobacterial genomes accommodate an exceptional number and variety of biosynthetic gene clusters (BGCs) which encode for features involved in specialized metabolism.MethodsIn this study, we describe the collection, sequencing, and genome mining of 20 myxobacteria isolated from rhizospheric soil samples collected in North America.ResultsNine isolates were determined to be novel species of myxobacteria including representatives from the genera Archangium, Myxococcus, Nannocystis, Polyangium, Pyxidicoccus, Sorangium, and Stigmatella. Growth profiles, biochemical assays, and descriptions were provided for all proposed novel species. We assess the BGC content of all isolates and observe differences between Myxococcia and Polyangiia clusters.DiscussionContinued discovery and sequencing of novel myxobacteria from the environment provide BGCs for the genome mining pipeline. Utilizing complete or near-complete genome sequences, we compare the chromosomal organization of BGCs of related myxobacteria from various genera and suggest that the spatial proximity of hybrid, modular clusters contributes to the metabolic adaptability of myxobacteria
Large-Scale Assessment of Binding Free Energy Calculations in Active Drug Discovery Projects
Here we present an evaluation of the binding affinity prediction accuracy of the free energy calculation method FEP+ on internal active drug discovery projects and on a large new public benchmark set.<br /
Discovery of Cycloalkyl[<i>c</i>]thiophenes as Novel Scaffolds for Hypoxia-Inducible Factor-2α Inhibitors
Hypoxia-inducible factors (HIFs) are heterodimeric transcription
factors induced in diverse pathophysiological settings. Inhibition
of HIF-2α has become a strategy for cancer treatment since the
discovery that small molecules, upon binding into a small cavity of
the HIF-2α PAS B domain, can alter its conformation and disturb
the activity of the HIF dimer complex. Herein, the design, synthesis,
and systematic SAR exploration of cycloalkyl[c]thiophenes
as novel HIF-2α inhibitors are described, providing the first
chemotype featuring an alkoxyâaryl scaffold. X-ray data confirmed
the ability of these inhibitors to induce perturbation of key amino
acids by appropriately presenting key pharmacophoric elements in the
hydrophobic cavity. Selected compounds showed inhibition of VEGF-A
secretion in cancer cells and prevention of Arg1 expression and activity
in IL4-stimulated macrophages. Moreover, in vivo target gene modulation
was demonstrated with compound 35r. Thus, the disclosed
HIF-2α inhibitors represent valuable tools for investigating
selective HIF-2α inhibition and its effect on tumor biology