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.

Computational systems pharmacology analysis of cannabidiol: a combination of chemogenomics-knowledgebase network analysis and integrated in silico modeling and simulation

“…Chemogenomics databases and tools Chemogenomics databases including the Cannabinoid Ligand Database (http://cbligand.org/cbid), Chemogenomics Database for Alzheimer's Disease [17] (http://cbligand.org/AD/), and Chemogenomics Database for Drug Abuse Research [18] (http://cbligand. org/CDAR/) were used for target prediction.…”

StemCellCKB: An Integrated Stem Cell-Specific Chemogenomics KnowledgeBase for Target Identification and Systems-Pharmacology Research

“…StemCellCKB facilitates stem cell relevant target identification by providing two integrated online programs: TargetHunter 30 and HTDocking. 24 To illustrate how the HTDocking component can be used to identify potential targets and explore mechanisms of action, we first validated our predictions using a set of known drug-target associations. Using the online StemCellCKB interface, we submitted SDF files describing a number of known small molecules (Figure 4A).…”

Neurochemistry of Abuse Liability Assessment and Primary Behavioral Correlates

“…In 2014, Xie et al [106] attempted to broadly explore the issue of "which" molecular mechanisms may play some role within the drug abuse scenario. for which there is no simple answer, and "Can a list be provided of 'all' the ligand binding targets of concern regarding abuse liability assessment?"…”