title: Identification of dual active agents targeting 5-HT1A and SERT by combinatorial virtual screening methods.
abstract: Selective serotonin reuptake inhibitors (SSRIs) are most adopted therapeutics marketed for major depression, and the efficacy of which are greatly reduced by their delayed onset of action and undesirable side effects. 5-HT1A receptor partial agonist and SERT inhibitor (SPARI) was proposed as a novel strategy to overcome the shortage of efficacy by a negative feedback control of 5-HT1A receptor. However, only one SPARI (vilazodone) has been approved for clinical use, and none is currently in clinical trial, which demonstrates a strong need for searching more novel SPARIs to facilitate antidepressants discovery. This work applied a combinatorial virtual screening method (CVSM) by integrating multiple tools. Statistic analysis reveals that CVSM surpasses single virtual screening methods in terms of hit rates and enrichment factors. By adopting optimized CVSM, 91 promising dual target leads form 15 scaffolds were identified, and 40% of these scaffolds have already been reported to show antidepressant related therapeutic effects. In sum, CVSM is capable in identifying novel SPARIs from large chemical libraries with extremely low false hit rate.
authors.affiliation: Innovative Drug Research Centre, Chongqing University, Chongqing, 401331, P.R. China.
authors.forename: Panpan
authors.initials: P
authors.lastname: Wang
authors.affiliation: Innovative Drug Research Centre, Chongqing University, Chongqing, 401331, P.R. China.
authors.forename: Fengyuan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Innovative Drug Research Centre, Chongqing University, Chongqing, 401331, P.R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.affiliation: Innovative Drug Research Centre, Chongqing University, Chongqing, 401331, P.R. China.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Xu
authors.affiliation: College of Computer Science, Chongqing University, Chongqing, 401331, P.R. China.
authors.forename: Duo
authors.initials: D
authors.lastname: Liu
authors.affiliation: Innovative Drug Research Centre, Chongqing University, Chongqing, 401331, P.R. China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Xue
authors.affiliation: Innovative Drug Research Centre, Chongqing University, Chongqing, 401331, P.R. China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhu
mesh_terms: D000928:Antidepressive Agents / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000737:chemistry* / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000928:Antidepressive Agents; D044282:Receptor, Serotonin, 5-HT1A; D058825:Serotonin 5-HT1 Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors
keywords: 5-HT1A receptor agonist; SERT inhibitor; Virtual screening; molecular docking; support vector machines