14 research outputs found
Large-Scale Mining for Similar Protein Binding Pockets: With RAPMAD Retrieval on the Fly Becomes Real
Determination of structural similarities
between protein binding
pockets is an important challenge in <i>in silico</i> drug
design. It can help to understand selectivity considerations, predict
unexpected ligand cross-reactivity, and support the putative annotation
of function to orphan proteins. To this end, Cavbase was developed
as a tool for the automated detection, storage, and classification
of putative protein binding sites. In this context, binding sites
are characterized as sets of pseudocenters, which denote surface-exposed
physicochemical properties, and can be used to enable mutual binding
site comparisons. However, these comparisons tend to be computationally
very demanding and often lead to very slow computations of the similarity
measures. In this study, we propose RAPMAD (RApid Pocket MAtching
using Distances), a new evaluation formalism for Cavbase entries that
allows for ultrafast similarity comparisons. Protein binding sites
are represented by sets of distance histograms that are both generated
and compared with linear complexity. Attaining a speed of more than
20 000 comparisons per second, screenings across large data sets and
even entire databases become easily feasible. We demonstrate the discriminative
power and the short runtime by performing several classification and
retrieval experiments. RAPMAD attains better success rates than the
comparison formalism originally implemented into Cavbase or several
alternative approaches developed in recent time, while requiring only
a fraction of their runtime. The pratical use of our method is finally
proven by a successful prospective virtual screening study that aims
for the identification of novel inhibitors of the NMDA receptor
Pyrazoles as NMDA NR2B receptor inhibitors and their preparation
The invention relates to pyrazole derivatives which are NMDA NR2B receptor inhibitors, useful in treating central o nervous system diseases
Synthesis, 18F-Radiolabelling and Biological Characterization of Novel Fluoroalkylated Triazine Derivatives for in Vivo Imaging of Phosphodiesterase 2A in Brain via Positron Emission Tomography
Phosphodiesterase 2A (PDE2A) is highly and specifically expressed in particular brain regions that are affected by neurological disorders and in certain tumors. Development of a specific PDE2A radioligand would enable molecular imaging of the PDE2A protein via positron emission tomography (PET). Herein we report on the syntheses of three novel fluoroalkylated triazine derivatives (TA2–4) and on the evaluation of their effect on the enzymatic activity of human PDE2A. The most potent PDE2A inhibitors were 18F-radiolabelled ([18F]TA3 and [18F]TA4) and investigated regarding their potential as PET radioligands for imaging of PDE2A in mouse brain. In vitro autoradiography on rat brain displayed region-specific distribution of [18F]TA3 and [18F]TA4, which is consistent with the expression pattern of PDE2A protein. Metabolism studies of both [18F]TA3 and [18F]TA4 in mice showed a significant accumulation of two major radiometabolites of each radioligand in brain as investigated by micellar radio-chromatography. Small-animal PET/MR studies in mice using [18F]TA3 revealed a constantly increasing uptake of activity in the non-target region cerebellum, which may be caused by the accumulation of brain penetrating radiometabolites. Hence, [18F]TA3 and [18F]TA4 are exclusively suitable for in vitro investigation of PDE2A. Nevertheless, further structural modification of these promising radioligands might result in metabolically stable derivatives
Investigation of an 18F-labelled Imidazopyridotriazine for Molecular Imaging of Cyclic Nucleotide Phosphodiesterase 2A
Specific radioligands for in vivo visualization and quantification of cyclic nucleotide phosphodiesterase 2A (PDE2A) by positron emission tomography (PET) are increasingly gaining interest in brain research. Herein we describe the synthesis, the 18F-labelling as well as the biological evaluation of our latest PDE2A (radio-)ligand 9-(5-Butoxy-2-fluorophenyl)-2-(2-([18F])fluoroethoxy)-7-methylimidazo[5,1-c]pyrido[2,3-e][1,2,4]triazine (([18F])TA5). It is the most potent PDE2A ligand out of our series of imidazopyridotriazine-based derivatives so far (IC50 hPDE2A = 3.0 nM; IC50 hPDE10A > 1000 nM). Radiolabelling was performed in a one-step procedure starting from the corresponding tosylate precursor. In vitro autoradiography on rat and pig brain slices displayed a homogenous and non-specific binding of the radioligand. Investigation of stability in vivo by reversed-phase HPLC (RP-HPLC) and micellar liquid chromatography (MLC) analyses of plasma and brain samples obtained from mice revealed a high fraction of one main radiometabolite. Hence, we concluded that [18F]TA5 is not appropriate for molecular imaging of PDE2A neither in vitro nor in vivo. Our ongoing work is focusing on further structurally modified compounds with enhanced metabolic stability