| 1. |
- Ballante, Flavio, et al.
(författare)
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Docking Finds GPCR Ligands in Dark Chemical Matter
- 2020
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 63:2, s. 613-620
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Tidskriftsartikel (refereegranskat)abstract
- High-throughput screening has revealed dark chemical matter, a set of drug-like compounds that has never shown bioactivity despite being extensively assayed. If dark molecules are found active at a therapeutic target, their extraordinary selectivity profiles make excellent starting points for drug development. We explored if ligands of therapeutically relevant G-protein-coupled receptors could be discovered by structure-based virtual screening of the dark chemical matter. Molecular docking screens against crystal structures of the A(2A) adenosine and the D-4 dopamine receptors were carried out, and 53 top-ranked molecules were evaluated experimentally. Two ligands of each receptor were discovered, and the most potent had sub-micromolar affinities. Analysis of bioactivity data showed that the ligands lacked activity at hundreds of off-targets, including several that are associated with adverse effects. Our results demonstrate that virtual screening provides an efficient means to mine the dark chemical space, which could contribute to development of drugs with improved safety profiles.
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| 2. |
- Jaiteh, Mariama, et al.
(författare)
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Docking Screens for Dual Inhibitors of Disparate Drug Targets for Parkinson's Disease
- 2018
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Ingår i: Journal of Medicinal Chemistry. - : AMER CHEMICAL SOC. - 0022-2623 .- 1520-4804. ; 61:12, s. 5269-5278
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Tidskriftsartikel (refereegranskat)abstract
- Modulation of multiple biological targets with a single drug can lead to synergistic therapeutic effects and has been demonstrated to be essential for efficient treatment of CNS disorders. However, rational design of compounds that interact with several targets is very challenging. Here, we demonstrate that structure-based virtual screening can guide the discovery of multi-target ligands of unrelated proteins relevant for Parkinson's disease. A library with 5.4 million molecules was docked to crystal structures of the A(2A) adenosine receptor (A(2A)AR) and monoamine oxidase B (MAO-B). Twenty-four compounds that were among the highest ranked for both binding sites were evaluated experimentally, resulting in the discovery of four dual-target ligands. The most potent compound was an A(2A)AR antagonist with nanomolar affinity (K-i = 19 nM) and inhibited MAO-B with an IC50 of 100 nM. Optimization guided by the predicted binding modes led to the identification of a second potent dual-target scaffold. The two discovered scaffolds were shown to counteract 6-hydroxydopamine-induced neurotoxicity in dopaminergic neuronal-like SH-SY5Y cells. Structure-based screening can hence be used to identify ligands with specific polypharmacological profiles, providing new avenues for drug development against complex diseases.
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| 3. |
- Mannel, Barbara, et al.
(författare)
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Structure-Guided Screening for Functionally Selective D-2 Dopamine Receptor Ligands from a Virtual Chemical Library
- 2017
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Ingår i: ACS Chemical Biology. - : AMER CHEMICAL SOC. - 1554-8929 .- 1554-8937. ; 12:10, s. 2652-2661
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Tidskriftsartikel (refereegranskat)abstract
- Functionally selective ligands stabilize conformations of G protein-coupled receptors (GPCRs) that induce a preference for signaling via a subset of the intracellular pathways activated by the endogenous agonists. The possibility to fine-tune the functional activity of a receptor provides opportunities to develop drugs that selectively signal via pathways associated with a therapeutic effect and avoid those causing side effects. Animal studies have indicated that ligands displaying functional selectivity at the D-2 dopamine receptor (D2R) could be safer and more efficacious drugs against neuropsychiatric diseases. In this work, computational design of functionally selective D2R ligands was explored using structure-based virtual screening. Molecular docking of known functionally selective ligands to a D2R homology model indicated that such compounds were anchored by interactions with the orthosteric site and extended into a common secondary pocket. A tailored virtual library with close to 13-000 compounds bearing 2,3-dichlorophenylpiperazine, a privileged orthosteric scaffold, connected to diverse chemical moieties via a linker was docked to the D2R model. Eighteen top-ranked compounds that occupied both the orthosteric and allosteric site were synthesized, leading to the discovery of 16 partial agonists. A majority of the ligands had comparable maximum effects in the G protein and beta-arrestin recruitment assays, but a subset displayed preference for a single pathway. In particular, compound 4 stimulated beta-arrestin recruitment (EC50 = 320 nM, E-max = 16%) but had no detectable G protein signaling. The use of structure-based screening and virtual libraries to discover GPCR ligands with tailored functional properties will be discussed.
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