Ligand Discovery from a Dopamine D3 Receptor Homology Model and Crystal Structure

By Jens Carlsson, Ryan G. Coleman, V. Setola, John J. Irwin, Hao Fan, Avner Schlessinger, Andrej Sali, Bryan L. Roth, Brian K. Shoichet. 2011

299 citations recorded by the source corpus.

G-Protein coupled receptors (GPCRs) are intensely studied as drug targets and for their role in signaling. With the determination of the first crystal structures, interest in structure-based ligand discovery has increased. Unfortunately, most GPCRs lack experimental structures. The determination of the D3 receptor structure, and a community challenge to predict it, enabled a fully prospective comparison of ligand discovery from a modeled structure versus that of the subsequently released crystal structure. Over 3.3 million molecules were docked against a homology model, and 26 of the highest ranking were tested for binding. Six had affinities from 0.2 to 3.1μM. Subsequently, the crystal structure was released and the docking screen repeated. Of the 25 compounds selected, five had affinities from 0.3 to 3.0μM. One of the novel ligands from the homology model screen was optimized for affinity to 81nM. The feasibility of docking screens against modeled GPCRs more generally is considered.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology, Computational Chemistry & Drug Discovery

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Citations in the corpus

A Role for Fragment-Based Drug Design in Developing Novel Lead Compounds for Central Nervous System Targets (2015, background): “Both models had comparable VS hit rates and showed no bias toward their respective templates (12).”
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Protein Modelling: What Happened to the “Protein Structure Gap”? (2013, unknown): “One class of proteins with particular interest for structure based drug discovery are GPCRs, where recent advances in experimental structure determination have brought a wide range of receptors within range for comparative modeling techniques (Carlsson et al., 2011; Kobilka and Schertler, 2008).”
Latest developments in molecular docking: 2010–2011 in review (2013, background): “[173] receptors; development of universal active probes;([162]) a comparison of Glide, Gold, and ICM-Pro for docking into the homology model of the 5-HT2A receptor; [165] and peptide docking with photoaffinity labeling constraints in ICM-Pro.”
How accurately can one predict drug binding modes using AlphaFold models? (2023, background): “An expert working on a drug discovery project could frequently build a better template-based model—for example, by examining the predictive utility of several models (Carlsson et al., 2011; Haddad et al., 2020).”
DREADDs for Neuroscientists (2016, background): “Additionally, my lab and collaborators have used these structures for the successful structure-guided discovery of novel small molecule modulators (Weiss et al., 2013; Carlsson et al., 2011; Shoichet and Kobilka, 2012; Huang et al., 2015c).”
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