6 research outputs found
Teach-Discover-Treat 2014, Part 2; Molecular Docking with DOCK 3.7
<p>Tutorial for TDT2014, part 2. Finding potential anti-malarial compounds with molecular docking. For more info see https://github.com/ryancoleman/tdt2014-part2</p
Small-Molecule Allosteric Modulators of the Protein Kinase PDK1 from Structure-Based Docking
Finding
small molecules that target allosteric sites remains a
grand challenge for ligand discovery. In the protein kinase field,
only a handful of highly selective allosteric modulators have been
found. Thus, more general methods are needed to discover allosteric
modulators for additional kinases. Here, we use virtual screening
against an ensemble of both crystal structures and comparative models
to identify ligands for an allosteric peptide-binding site on the
protein kinase PDK1 (the PIF pocket). We optimized these ligands through
an analog-by-catalog search that yielded compound <b>4</b>,
which binds to PDK1 with 8 μM affinity. We confirmed the docking
poses by determining a crystal structure of PDK1 in complex with <b>4</b>. Because the PIF pocket appears to be a recurring structural
feature of the kinase fold, known generally as the helix αC
patch, this approach may enable the discovery of allosteric modulators
for other kinases
Selectivity Challenges in Docking Screens for GPCR Targets and Antitargets
To
investigate large library docking’s 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, κ-opioid receptor ligands
were sought with selectivity versus the μ-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 docking’s 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, κ-opioid receptor ligands
were sought with selectivity versus the μ-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 docking’s 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, κ-opioid receptor ligands
were sought with selectivity versus the μ-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 docking’s 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, κ-opioid receptor ligands
were sought with selectivity versus the μ-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