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. 2018 Aug 9;61(15):6830-6845.
doi: 10.1021/acs.jmedchem.8b00718. Epub 2018 Jul 24.

Selectivity Challenges in Docking Screens for GPCR Targets and Antitargets

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Free PMC article

Selectivity Challenges in Docking Screens for GPCR Targets and Antitargets

Dahlia R Weiss et al. J Med Chem. .
Free PMC article

Abstract

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-HT2A 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-HT2A 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.

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Docking-prioritized homology models superpose well on subsequently determined crystal structures (0.9–1 Å all atom binding site rmsd). (A) Binding site of the DRD2-risperidone cocrystal structure (PDB code 6MC4, green) superposition based on all receptor atom overlay on the docking-prioritized homology model used in the docking screens (magenta). (B) Binding site of HTR2B ergotamine cocrystal structure (PDB code 4IB4, orange) superposition based on all receptor atoms overlaid on the docking-prioritized homology model used in the docking screen (cyan).
Figure 2
Figure 2
Docking can predict dual-binders for on-targets but cannot reliably predict nonbinders for an antitarget. (A–C) Cut-away view of the orthosteric binding sites for HTR2A model with LSD bound; DRD2 model with eticlopride bound; HRH1 cocrystal structure with doxepin. (D–F) Docked pose of the most selective compound, compound 21, to HTR2A; DRD2; HRH1. Clashes with the HRH1 crystal structure are shown as red circles. (H–J) Docked pose of the least selective compound, compound 6, docked to HTR2A; DRD2; HRH1. Clashes with the HRH1 crystal structure are shown as red circles.
Figure 3
Figure 3
Radioligand displacement binding affinities for HTR2A, DRD2, and HRH1. Reference ligands are [3H]ketanserin, [3H]N-methylspiperone, and [3H]pyrilamine, respectively. (Top) Specific binding of the 20-fold selective docking hit, compound 21. (Bottom) Compound 6, a molecule that was both a docking false-positive (it does not bind to the on-targets HTR2A and DRD2) and a false-negative (it does bind to the off-target HRH1 with subnanomolar affinity).
Figure 4
Figure 4
KOR and MOR binding sites. (A) Orthosteric sites for KOR (left) and MOR (right), with their respective cocrystallized ligand. The residues shown as sticks were those used to discriminate predicted selective compounds. (B) A selective compound, 2, is shown in the docked pose to KOR (left) and MOR (right).
Figure 5
Figure 5
Visual summary of the initial screen of 28 molecules tested against the HT2RA, DRD2, and HRH1 receptors.
Figure 6
Figure 6
Venn diagram of annotated ChEMBL ligands for the three targets.

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