3 research outputs found
Interacting with GPCRs: Using Interaction Fingerprints for Virtual Screening
The expanding number
of crystal structures of G protein-coupled
receptors (GPCRs) has increased the knowledge on receptor function
and their ability to recognize ligands. Although structure-based virtual
screening has been quite successful on GPCRs, scores obtained by docking
are typically not indicative for ligand affinity. Methods capturing
interactions between protein and ligand in a more explicit manner,
such as interaction fingerprints (IFPs), have been applied as an addition
or alternative to docking. Originally IFPs captured the interactions
of amino acid residues with ligands with specific definitions for
the various interaction types. More complex IFPs now capture atomâatom
interactions, such as in SYBYL, or fragmentâfragment co-occurrences
such as in SPLIF. Overall, most of the IFPs have been studied in comparison
with docking in retrospective studies. For GPCRs it remains unclear
which IFP should be used, if at all, and in what manner. Thus, the
performance between five different IFPs was compared on five different
representative GPCRs, including several extensions of the original
implementations,. Results show that the more detailed IFPs, SYBYL
and SPLIF, perform better than the other IFPs (Deng, Credo, and Elements).
SPLIF was further tuned based on the number of poses, fingerprint
similarity coefficient, and using an ensemble of structures. Enrichments
were obtained that were significantly higher than initial enrichments
and those obtained by 2D-similarity. With the increase in available
crystal structures for GPCRs, and given that IFPs such as SPLIF enhance
enrichment in virtual screens, it is anticipated that IFPs will be
used in conjunction with docking, especially for GPCRs with a large
binding pocket
Effect of Nitrogen Atom Substitution in A<sub>3</sub> Adenosine Receptor Binding: <i>N</i>â(4,6-Diarylpyridin-2-yl)acetamides as Potent and Selective Antagonists
We
report the first family of 2-acetamidopyridines as potent and
selective A<sub>3</sub> adenosine receptor (AR) antagonists. The computer-assisted
design was focused on the bioisosteric replacement of the N1 atom
by a CH group in a previous series of diarylpyrimidines. Some of the
generated 2-acetamidopyridines elicit an antagonistic effect with
excellent affinity (<i>K</i><sub>i</sub> < 10 nM) and
outstanding selectivity profiles, providing an alternative and simpler
chemical scaffold to the parent series of diarylpyrimidines. In addition,
using molecular dynamics and free energy perturbation simulations,
we elucidate the effect of the second nitrogen of the parent diarylpyrimidines,
which is revealed as a stabilizer of a water network in the binding
site. The discovery of 2,6-diaryl-2-acetamidopyridines represents
a step forward in the search of chemically simple, potent, and selective
antagonists for the hA<sub>3</sub>AR, and exemplifies the benefits
of a joint theoreticalâexperimental approach to identify novel
hA<sub>3</sub>AR antagonists through succinct and efficient synthetic
methodologies
Effect of Nitrogen Atom Substitution in A<sub>3</sub> Adenosine Receptor Binding: <i>N</i>â(4,6-Diarylpyridin-2-yl)acetamides as Potent and Selective Antagonists
We
report the first family of 2-acetamidopyridines as potent and
selective A<sub>3</sub> adenosine receptor (AR) antagonists. The computer-assisted
design was focused on the bioisosteric replacement of the N1 atom
by a CH group in a previous series of diarylpyrimidines. Some of the
generated 2-acetamidopyridines elicit an antagonistic effect with
excellent affinity (<i>K</i><sub>i</sub> < 10 nM) and
outstanding selectivity profiles, providing an alternative and simpler
chemical scaffold to the parent series of diarylpyrimidines. In addition,
using molecular dynamics and free energy perturbation simulations,
we elucidate the effect of the second nitrogen of the parent diarylpyrimidines,
which is revealed as a stabilizer of a water network in the binding
site. The discovery of 2,6-diaryl-2-acetamidopyridines represents
a step forward in the search of chemically simple, potent, and selective
antagonists for the hA<sub>3</sub>AR, and exemplifies the benefits
of a joint theoreticalâexperimental approach to identify novel
hA<sub>3</sub>AR antagonists through succinct and efficient synthetic
methodologies