title: Chemogenomics knowledgebased polypharmacology analyses of drug abuse related G-protein coupled receptors and their ligands.
abstract: Drug abuse (DA) and addiction is a complex illness, broadly viewed as a neurobiological impairment with genetic and environmental factors that influence its development and manifestation. Abused substances can disrupt the activity of neurons by interacting with many proteins, particularly G-protein coupled receptors (GPCRs). A few medicines that target the central nervous system (CNS) can also modulate DA related proteins, such as GPCRs, which can act in conjunction with the controlled psychoactive substance(s) and increase side effects. To fully explore the molecular interaction networks that underlie DA and to effectively modulate the GPCRs in these networks with small molecules for DA treatment, we built a drug-abuse domain specific chemogenomics knowledgebase (DA-KB) to centralize the reported chemogenomics research information related to DA and CNS disorders in an effort to benefit researchers across a broad range of disciplines. We then focus on the analysis of GPCRs as many of them are closely related with DA. Their distribution in human tissues was also analyzed for the study of side effects caused by abused drugs. We further implement our computational algorithms/tools to explore DA targets, DA mechanisms and pathways involved in polydrug addiction and to explore polypharmacological effects of the GPCR ligands. Finally, the polypharmacology effects of GPCRs-targeted medicines for DA treatment were investigated and such effects can be exploited for the development of drugs with polypharmacophore for DA intervention. The chemogenomics database and the analysis tools will help us better understand the mechanism of drugs abuse and facilitate to design new medications for system pharmacotherapy of DA.
authors.affiliation: Department of Pharmaceutical Sciences, Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh Pittsburgh, PA, USA ; Center for Chemical Methodologies and Library Development (UPCMLD) and Department of Chemistry, University of Pittsburgh Pittsburgh, PA, USA ; Drug Discovery Institute, University of Pittsburgh Pittsburgh, PA, USA ; Departments of Computational and Systems Biology, University of Pittsburgh Pittsburgh, PA, USA.
authors.forename: Xiang-Qun
authors.initials: XQ
authors.lastname: Xie
authors.affiliation: Department of Pharmaceutical Sciences, Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh Pittsburgh, PA, USA ; Center for Chemical Methodologies and Library Development (UPCMLD) and Department of Chemistry, University of Pittsburgh Pittsburgh, PA, USA ; Drug Discovery Institute, University of Pittsburgh Pittsburgh, PA, USA.
authors.forename: Lirong
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Sciences, Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh Pittsburgh, PA, USA ; Guangzhou Quality R&D Center of Traditional Chinese Medicine, School of Life Sciences, Sun Yat-Sen University Guangzhou, China.
authors.forename: Haibin
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutical Sciences, Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh Pittsburgh, PA, USA ; Center for Chemical Methodologies and Library Development (UPCMLD) and Department of Chemistry, University of Pittsburgh Pittsburgh, PA, USA ; Drug Discovery Institute, University of Pittsburgh Pittsburgh, PA, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Ouyang
authors.affiliation: Department of Pharmaceutical Sciences, Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh Pittsburgh, PA, USA ; Center for Chemical Methodologies and Library Development (UPCMLD) and Department of Chemistry, University of Pittsburgh Pittsburgh, PA, USA ; Drug Discovery Institute, University of Pittsburgh Pittsburgh, PA, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Fang
authors.affiliation: Guangzhou Quality R&D Center of Traditional Chinese Medicine, School of Life Sciences, Sun Yat-Sen University Guangzhou, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Su
keywords: GPCRs; chemogenomics; cloud computation; drug abuse; polydrug addiction; polypharmacology; systems pharmacology; target prediction