14 research outputs found
Sequence analysis of the cis-regulatory regions of the bithorax complex of Drosophila
The bithorax complex (BX-C) of Drosophila, one of two complexes that act as master regulators of the body plan of the fly, has now been entirely sequenced and comprises approximate to 315,000 bp, only 1.4% of which codes for protein. Analysis of this sequence reveals significantly overrepresented DNA motifs of unknown, as well as known, functions in the nonprotein-coding portion of the sequence. The following types of motifs in that portion are analyzed: (i) concatamers of mono-, di-, and trinucleotides; (ii) tightly clustered hexanucleotides (spaced less than or equal to 5 bases apart); (iii) direct and reverse repeats longer than 20 bp; and (iv) a number of motifs known from biochemical studies to play a role in the regulation of the BX-C. The hexanucleotide AGATAC is remarkably overrepresented and is surmised to play a role in chromosome pairing. The positions of sites of highly overrepresented motifs are plotted for those that occur at more than five sites in the sequence, when <0.5 case is expected. Expected values are based on a third-order Markov chain, which is the optimal order for representing the BXCALL sequence
A Novel Binding Mode Reveals Two Distinct Classes of NMDA Receptor GluN2B-selective Antagonists
Discovery of Tyrosine Kinase 2 (TYK2) Inhibitor (PF-06826647) for the Treatment of Autoimmune Diseases
Siderophore Receptor-Mediated Uptake of Lactivicin Analogues in Gram-Negative Bacteria
Multidrug-resistant Gram-negative
pathogens are an emerging threat
to human health, and addressing this challenge will require development
of new antibacterial agents. This can be achieved through an improved
molecular understanding of drug–target interactions combined
with enhanced delivery of these agents to the site of action. Herein
we describe the first application of siderophore receptor-mediated
drug uptake of lactivicin analogues as a strategy that enables the
development of novel antibacterial agents against clinically relevant
Gram-negative bacteria. We report the first crystal structures of
several sideromimic conjugated compounds bound to penicillin binding
proteins PBP3 and PBP1a from <i>Pseudomonas aeruginosa</i> and characterize the reactivity of lactivicin and β-lactam
core structures. Results from drug sensitivity studies with β-lactamase
enzymes are presented, as well as a structure-based hypothesis to
reduce susceptibility to this enzyme class. Finally, mechanistic studies
demonstrating that sideromimic modification alters the drug uptake
process are discussed
Pyrimidone-based series of glucokinase activators with alternative donor–acceptor motif
Azetidine and Piperidine Carbamates as Efficient, Covalent Inhibitors of Monoacylglycerol Lipase
Monoacylglycerol
lipase (MAGL) is the main enzyme responsible for
degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG) in
the CNS. MAGL catalyzes the conversion of 2-AG to arachidonic acid
(AA), a precursor to the proinflammatory eicosannoids such as prostaglandins.
Herein we describe highly efficient MAGL inhibitors, identified through
a parallel medicinal chemistry approach that highlighted the improved
efficiency of azetidine and piperidine-derived carbamates. The discovery
and optimization of 3-substituted azetidine carbamate irreversible
inhibitors of MAGL were aided by the generation of inhibitor-bound
MAGL crystal structures. Compound <b>6</b>, a highly efficient
and selective MAGL inhibitor against recombinant enzyme and in a cellular
context, was tested in vivo and shown
to elevate central 2-AG levels at a 10 mg/kg dose
Discovery of Fragment-Derived Small Molecules for in Vivo Inhibition of Ketohexokinase (KHK)
Increased
fructose consumption and its subsequent metabolism have
been implicated in hepatic steatosis, dyslipidemia, obesity, and insulin
resistance in humans. Since ketohexokinase (KHK) is the principal
enzyme responsible for fructose metabolism, identification of a selective
KHK inhibitor may help to further elucidate the effect of KHK inhibition
on these metabolic disorders. Until now, studies on KHK inhibition
with small molecules have been limited due to the lack of viable in
vivo pharmacological tools. Herein we report the discovery of <b>12</b>, a selective KHK inhibitor with potency and properties
suitable for evaluating KHK inhibition in rat models. Key structural
features interacting with KHK were discovered through fragment-based
screening and subsequent optimization using structure-based drug design,
and parallel medicinal chemistry led to the identification of pyridine <b>12</b>
Potent Inhibitors of LpxC for the Treatment of Gram-Negative Infections
In this paper, we present the synthesis and SAR as well
as selectivity, pharmacokinetic, and infection model data for representative
analogues of a novel series of potent antibacterial LpxC inhibitors
represented by hydroxamic acid <b>1a</b>