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 D₂ and serotonin 5-HT_2A receptors were targeted, seeking selectivity against the histamine H₁ 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 D₂/5-HT_2A ligand with 21-fold selectivity versus the H₁ 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 D₂ and serotonin 5-HT_2A receptors were targeted, seeking selectivity against the histamine H₁ 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 D₂/5-HT_2A ligand with 21-fold selectivity versus the H₁ 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 D₂ and serotonin 5-HT_2A receptors were targeted, seeking selectivity against the histamine H₁ 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 D₂/5-HT_2A ligand with 21-fold selectivity versus the H₁ 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 D₂ and serotonin 5-HT_2A receptors were targeted, seeking selectivity against the histamine H₁ 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 D₂/5-HT_2A ligand with 21-fold selectivity versus the H₁ 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