ArticleBioorganic & medicinal chemistry letters2016
Ligand-based virtual screen for the discovery of novel M5 inhibitor chemotypes.
Article in Bioorganic & medicinal chemistry letters, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- A New Era of Muscarinic Acetylcholine Receptor Modulators in Neurological Diseases, Cancer and Drug Abuse.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Artificial intelligence and machine-learning approaches in structure and ligand-based discovery of drugs affecting central nervous system.Molecular diversity · 2023Review
- Discovery of a potent MBioorganic & medicinal chemistry letters · 2022Article
- Artificial intelligence and machine learning-aided drug discovery in central nervous system diseases: State-of-the-arts and future directions.Medicinal research reviews · 2021Review
- General Purpose Structure-Based Drug Discovery Neural Network Score Functions with Human-Interpretable Pharmacophore Maps.Journal of chemical information and modeling · 2021Article
- Examining the role of muscarinic M5 receptors in VTA cholinergic modulation of depressive-like and anxiety-related behaviors in rats.Neuropharmacology · 2020Article
- Large-Scale Target Identification of Herbal Medicine Using a Reverse Docking Approach.ACS omega · 2019Article
- A qualitatively validated mathematical-computational model of the immune response to the yellow fever vaccine.BMC immunology · 2018Article
- Discovery and optimization of 3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazines as novel, CNS penetrant pan-muscarinic antagonists.Bioorganic & medicinal chemistry letters · 2017Article
- Synthesis and evaluation of 4,6-disubstituted pyrimidines as CNS penetrant pan-muscarinic antagonists with a novel chemotype.Bioorganic & medicinal chemistry letters · 2017Article
- Continued optimization of the MBioorganic & medicinal chemistry letters · 2017Article
- Mathematical modeling based on ordinary differential equations: A promising approach to vaccinology.Human vaccines & immunotherapeutics · 2017Article
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Authors and funding
8 authors.
Funding
Abstract
This Letter describes a ligand-based virtual screening campaign utilizing SAR data around the M5 NAMs, ML375 and VU6000181. Both QSAR and shape scores were employed to virtually screen a 98,000-member compound library. Neither approach alone proved productive, but a consensus score of the two models identified a novel scaffold which proved to be a modestly selective, but weak inhibitor (VU0549108) of the M5 mAChR (M5 IC50=6.2μM, M1-4 IC50s>10μM) based on an unusual 8-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)-1-oxa-4-thia-8-azaspiro[4,5]decane scaffold. [(3)H]-NMS binding studies showed that VU0549108 interacts with the orthosteric site (Ki of 2.7μM), but it is not clear if this is negative cooperativity or orthosteric binding. Interestingly, analogs synthesized around VU0549108 proved weak, and SAR was very steep. However, this campaign validated the approach and warranted further expansion to identify additional novel chemotypes.
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