title: Ligand-based virtual screen for the discovery of novel M5 inhibitor chemotypes.
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.
authors: Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
authors: Alexander R
authors: AR
authors: Geanes
authors: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors: Hykeyung P
authors: HP
authors: Cho
authors: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
authors: Kellie D
authors: KD
authors: Nance
authors: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors: Kevin M
authors: KM
authors: McGowan
authors: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Center for Addiction Research, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors: P Jeffrey
authors: PJ
authors: Conn
authors: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Center for Addiction Research, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors: Carrie K
authors: CK
authors: Jones
authors: Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: jens.meiler@vanderbilt.edu.
authors: Jens
authors: J
authors: Meiler
authors: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Addiction Research, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address: craig.lindsley@vanderbilt.edu.
authors: Craig W
authors: CW
authors: Lindsley
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D055808:Drug Discovery; D006801:Humans; D008024:Ligands; D018727:Muscarinic Antagonists / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D043642:Receptor, Muscarinic M5 / Q000037:antagonists & inhibitors*
chemical_list: D008024:Ligands; D018727:Muscarinic Antagonists; D043642:Receptor, Muscarinic M5
keywords: M(5); Muscarinic acetylcholine receptor; Structure–activity relationship (SAR); Virtual screen