Polypharmacological Drugs: “Magic Shotguns” for Psychiatric Diseases

Kroeze, Wesley K.; Roth, Bryan L.

doi:10.1002/9781118098141.ch7

Cited by 13 publications

(19 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The atypical antipsychotic drug clozapine, for example, shows antagonist activity at multiple aminergic GPCR family, such as the 5HT, dopamine, muscarinic, histamine, and adrenergic receptors, some of which are associated with efficacy and others with side effects (Morphy et al, 2004 ; Morphy, 2012 ). More examples can be found in the current literature (Kroeze and Roth, 2012 ). Another important consideration is that DA and addiction often co-occur with other mental illnesses (Regier et al, 1990 ).…”

Section: Introductionmentioning

confidence: 98%

Chemogenomics knowledgebased polypharmacology analyses of drug abuse related G-protein coupled receptors and their ligands

Xie¹,

Wang²,

Liu³

et al. 2014

Front. Pharmacol.

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 98%

Chemogenomics knowledgebased polypharmacology analyses of drug abuse related G-protein coupled receptors and their ligands

Xie¹,

Wang²,

Liu³

et al. 2014

Front. Pharmacol.

View full text Add to dashboard Cite

show abstract

“…Ligand-based in silico screening can help to address part of this challenge by providing a means to rapidly search a vast chemical space for bioactive compounds with a promiscuous binding profile [ 17 , 18 , 19 , 20 ]. When designed to exploit the chemical information of known ligands, it can identify patterns associated with receptor interactions in an automated fashion without any knowledge of a receptor’s 3D structure [ 17 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

An Integrated Approach toward NanoBRET Tracers for Analysis of GPCR Ligand Engagement

et al. 2021

View full text Add to dashboard Cite

Gaining insight into the pharmacology of ligand engagement with G-protein coupled receptors (GPCRs) under biologically relevant conditions is vital to both drug discovery and basic research. NanoLuc-based bioluminescence resonance energy transfer (NanoBRET) monitoring competitive binding between fluorescent tracers and unmodified test compounds has emerged as a robust and sensitive method to quantify ligand engagement with specific GPCRs genetically fused to NanoLuc luciferase or the luminogenic HiBiT peptide. However, development of fluorescent tracers is often challenging and remains the principal bottleneck for this approach. One way to alleviate the burden of developing a specific tracer for each receptor is using promiscuous tracers, which is made possible by the intrinsic specificity of BRET. Here, we devised an integrated tracer discovery workflow that couples machine learning-guided in silico screening for scaffolds displaying promiscuous binding to GPCRs with a blend of synthetic strategies to rapidly generate multiple tracer candidates. Subsequently, these candidates were evaluated for binding in a NanoBRET ligand-engagement screen across a library of HiBiT-tagged GPCRs. Employing this workflow, we generated several promiscuous fluorescent tracers that can effectively engage multiple GPCRs, demonstrating the efficiency of this approach. We believe that this workflow has the potential to accelerate discovery of NanoBRET fluorescent tracers for GPCRs and other target classes.

show abstract

“…Examples of effective multitarget drugs include aspirin (inflammation) and various selective serotonin reuptake inhibitors (SSRIs; depression) and imatinib (cancer). 5 − 10 …”

Section: Introductionmentioning

confidence: 99%

“…A chemical proteomics approach based on Kinobead technology has proved to be important in the development of a kinase inhibitor target and off-target profile, confirming the polypharmacology of many clinical drugs. 5 − 7 , 10 , 19 , 20 …”

Section: Introductionmentioning

confidence: 99%

FD5180, a Novel Protein Kinase Affinity Probe, and the Effect of Bead Loading on Protein Kinase Identification

et al. 2017

View full text Add to dashboard Cite

The effects of compound loading on the identification of protein kinases (PKs) was examined using two previously reported sepharose-supported PK inhibitors (PKIs): bisindolylmaleimide X (S1) and CZC8004 (S2). Compound loadings of 0.1, 0.5, 2.5, 5, 10, 25, and 50% content and an ethanolamine-blocked control bead (no compound) were investigated. A 50% bead loading gave the highest level of PK identification for both S1 and S2, extracting 34 and 55 PKs, respectively, from a single cell lysate. Control beads allowed overall identification of 23 PKs, which we term the kinase beadome, whereas sepharose-supported sunitinib (S7; 50% loading) identified 20, 11 of which were common to the control beads. The reliability of bead pull-downs was examined in duplicate experiments using two independently synthesized batches each of S1 and S2. Bead S1 showed high similarity in the absolute numbers of PKs identified across two experiments, at 40 and 35 PKs, of which 26 were common across the two batches of beads, with 14 and 9 unique PKs identified in each experiment. The S2 beads extracted 61 and 64 PKs with 55 PKs common across the two bead batches examined. We also report on the development and use of a novel promiscuous PKI analogue, 2-[(5-chloro-2{[4-(piperazin-1-yl)phenyl]amino}pyrimidin-4-yl)amino]-N-methylbenzene-sulfonamide (S15), which extracted 12 additional unique PKs over the two parent compounds from which it was designed, the combination of which identifies 160 unique PKs. S15 was based on the common pyrimidine core scaffold of S9 and S10. Thus, S15 expands the utility of kinobeads by broadening the kinome coverage for bead-based pull-down. Combining the data for all beads across 90 and 180 min liquid chromatography–mass spectrometry (LC–MS)/MS analysis identified a total of 160 unique PKs.

show abstract

Polypharmacological Drugs: “Magic Shotguns” for Psychiatric Diseases

Cited by 13 publications

References 45 publications

Chemogenomics knowledgebased polypharmacology analyses of drug abuse related G-protein coupled receptors and their ligands

Chemogenomics knowledgebased polypharmacology analyses of drug abuse related G-protein coupled receptors and their ligands

An Integrated Approach toward NanoBRET Tracers for Analysis of GPCR Ligand Engagement

FD5180, a Novel Protein Kinase Affinity Probe, and the Effect of Bead Loading on Protein Kinase Identification

Contact Info

Product

Resources

About