35 research outputs found
Structure-Based Discovery of Novel and Selective 5âHydroxytryptamine 2B Receptor Antagonists for the Treatment of Irritable Bowel Syndrome
Here
we employed structure-based ligand discovery techniques to
explore a recently determined crystal structure of the 5-hydroxytryptamine
2B (5-HT<sub>2B</sub>) receptor. Ten compounds containing a novel
chemical scaffold were identified; among them, seven molecules were
active in cellular function assays with the most potent one exhibiting
an IC<sub>50</sub> value of 27.3 nM. We then systematically probed
the binding characteristics of this scaffold by designing, synthesizing,
and testing a series of structural modifications. The structureâactivity
relationship studies strongly support our predicted binding model.
The binding profiling across a panel of 11 5-HT receptors indicated
that these compounds are highly selective for the 5-HT<sub>2B</sub> receptor. Oral administration of compound <b>15</b> (30 mg/kg)
produced significant attenuation of visceral hypersensitivity in a
rat model of irritable bowel syndrome (IBS). We expect this novel
scaffold will serve as the foundation for the development of 5-HT<sub>2B</sub> antagonists for the treatment of IBS
Heterotropic Cooperativity within and between Protomers of an Oligomeric M<sub>2</sub> Muscarinic Receptor
At least four allosteric sites have been found to mediate
the dose-dependent
effects of gallamine on the binding of [<sup>3</sup>H]Âquinuclidinylbenzilate
(QNB) and <i>N</i>-[<sup>3</sup>H]Âmethylscopolamine (NMS)
to M<sub>2</sub> muscarinic receptors in membranes and solubilized
preparations from porcine atria, CHO cells, and <i>Sf</i>9 cells. The rate of dissociation of [<sup>3</sup>H]ÂQNB was affected
in a bell-shaped manner with at least one Hill coefficient (<i>n</i><sub>H</sub>) greater than 1, indicating that at least
three allosteric sites are involved. The level of binding of [<sup>3</sup>H]ÂQNB was decreased in a biphasic manner, revealing at least
two allosteric sites; binding of [<sup>3</sup>H]ÂNMS was affected in
a triphasic, serpentine manner, revealing at least three sites, and
values of <i>n</i><sub>H</sub> >1 pointed to at least
four
sites. Several lines of evidence indicate that all effects of gallamine
were allosteric in nature and could be observed at equilibrium. The
rates of equilibration and dissociation suggest that the receptor
was predominately oligomeric, and the heterogeneity revealed by gallamine
can be attributed to differences in its affinity for the constituent
protomers of a tetramer. Those differences appear to arise from inter-
and intramolecular cooperativity between gallamine and the radioligand
A Simple Representation of Three-Dimensional Molecular Structure
Statistical
and machine learning approaches predict drug-to-target
relationships from 2D small-molecule topology patterns. One might
expect 3D information to improve these calculations. Here we apply
the logic of the extended connectivity fingerprint (ECFP) to develop
a rapid, alignment-invariant 3D representation of molecular conformers,
the extended three-dimensional fingerprint (E3FP). By integrating
E3FP with the similarity ensemble approach (SEA), we achieve higher
precision-recall performance relative to SEA with ECFP on ChEMBL20
and equivalent receiver operating characteristic performance. We identify
classes of molecules for which E3FP is a better predictor of similarity
in bioactivity than is ECFP. Finally, we report novel drug-to-target
binding predictions inaccessible by 2D fingerprints and confirm three
of them experimentally with ligand efficiencies from 0.442â0.637
kcal/mol/heavy atom
Mesh plot summarizing pharmacology of 3 novel PCP analogues.
<p>Shown in three dimensional mesh plot format are the pKi values of the three novel PCP analogues (3-MeO-PCE, 3-MeO-phencyclidine and 4-MeO-phencyclidine; 1, 2 and 3 respectively) against a panel of 56 molecular targets.</p
Chemical structures of ketamine, methoxetamine, phencyclidine and analogues.
<p>Chemical structures of ketamine, methoxetamine, phencyclidine and analogues.</p
Selectivity Challenges in Docking Screens for GPCR Targets and Antitargets
To
investigate large library dockingâs ability to find molecules
with joint activity against on-targets and selectivity versus antitargets,
the dopamine D<sub>2</sub> and serotonin 5-HT<sub>2A</sub> receptors
were targeted, seeking selectivity against the histamine H<sub>1</sub> receptor. In a second campaign, Îș-opioid receptor ligands
were sought with selectivity versus the Ό-opioid receptor. While
hit rates ranged from 40% to 63% against the on-targets, they were
just as good against the antitargets, even though the molecules were
selected for their putative lack of binding to the off-targets. Affinities,
too, were often as good or better for the off-targets. Even though
it was occasionally possible to find selective molecules, such as
a mid-nanomolar D<sub>2</sub>/5-HT<sub>2A</sub> ligand with 21-fold
selectivity versus the H<sub>1</sub> receptor, this was the exception.
Whereas false-negatives are tolerable in docking screens against on-targets,
they are intolerable against antitargets; addressing this problem
may demand new strategies in the field
Selectivity Challenges in Docking Screens for GPCR Targets and Antitargets
To
investigate large library dockingâs ability to find molecules
with joint activity against on-targets and selectivity versus antitargets,
the dopamine D<sub>2</sub> and serotonin 5-HT<sub>2A</sub> receptors
were targeted, seeking selectivity against the histamine H<sub>1</sub> receptor. In a second campaign, Îș-opioid receptor ligands
were sought with selectivity versus the Ό-opioid receptor. While
hit rates ranged from 40% to 63% against the on-targets, they were
just as good against the antitargets, even though the molecules were
selected for their putative lack of binding to the off-targets. Affinities,
too, were often as good or better for the off-targets. Even though
it was occasionally possible to find selective molecules, such as
a mid-nanomolar D<sub>2</sub>/5-HT<sub>2A</sub> ligand with 21-fold
selectivity versus the H<sub>1</sub> receptor, this was the exception.
Whereas false-negatives are tolerable in docking screens against on-targets,
they are intolerable against antitargets; addressing this problem
may demand new strategies in the field
Selectivity Challenges in Docking Screens for GPCR Targets and Antitargets
To
investigate large library dockingâs ability to find molecules
with joint activity against on-targets and selectivity versus antitargets,
the dopamine D<sub>2</sub> and serotonin 5-HT<sub>2A</sub> receptors
were targeted, seeking selectivity against the histamine H<sub>1</sub> receptor. In a second campaign, Îș-opioid receptor ligands
were sought with selectivity versus the Ό-opioid receptor. While
hit rates ranged from 40% to 63% against the on-targets, they were
just as good against the antitargets, even though the molecules were
selected for their putative lack of binding to the off-targets. Affinities,
too, were often as good or better for the off-targets. Even though
it was occasionally possible to find selective molecules, such as
a mid-nanomolar D<sub>2</sub>/5-HT<sub>2A</sub> ligand with 21-fold
selectivity versus the H<sub>1</sub> receptor, this was the exception.
Whereas false-negatives are tolerable in docking screens against on-targets,
they are intolerable against antitargets; addressing this problem
may demand new strategies in the field
Selectivity Challenges in Docking Screens for GPCR Targets and Antitargets
To
investigate large library dockingâs ability to find molecules
with joint activity against on-targets and selectivity versus antitargets,
the dopamine D<sub>2</sub> and serotonin 5-HT<sub>2A</sub> receptors
were targeted, seeking selectivity against the histamine H<sub>1</sub> receptor. In a second campaign, Îș-opioid receptor ligands
were sought with selectivity versus the Ό-opioid receptor. While
hit rates ranged from 40% to 63% against the on-targets, they were
just as good against the antitargets, even though the molecules were
selected for their putative lack of binding to the off-targets. Affinities,
too, were often as good or better for the off-targets. Even though
it was occasionally possible to find selective molecules, such as
a mid-nanomolar D<sub>2</sub>/5-HT<sub>2A</sub> ligand with 21-fold
selectivity versus the H<sub>1</sub> receptor, this was the exception.
Whereas false-negatives are tolerable in docking screens against on-targets,
they are intolerable against antitargets; addressing this problem
may demand new strategies in the field