Computational Systems Pharmacology-Target Mapping for Fentanyl-Laced Cocaine Overdose

Abstract

The United States of America is fighting against one of its worst-ever drug crises. Over 900 people a week die from opioid-or heroin-related overdoses, while millions more suffer from opioid prescription addiction. Recently, drug overdoses caused by fentanyl-laced cocaine specifically are on the rise. Due to drug synergy and an increase in side effects, polydrug addiction can cause more risk than addiction to a single drug. In the present work, we systematically analyzed the overdose and addiction mechanism of cocaine and fentanyl. First, we applied our established chemogenomics knowledgebase and machine-learning-based methods to map out the potential and known proteins, transporters, and metabolic enzymes and the potential therapeutic target(s) for cocaine and fentanyl. Sequentially, we looked into the detail of (1) the addiction to cocaine and fentanyl by binding to the dopamine transporter and the μ opioid receptor (DAT and μOR, respectively), (2) the potential drug−drug interaction of cocaine and fentanyl via p-glycoprotein (P-gp) efflux, (3) the metabolism of cocaine and fentanyl in CYP3A4, and (4) the physiologically based pharmacokinetic (PBPK) model for two drugs and their drug−drug interaction at the absorption, distribution, metabolism, and excretion (ADME) level. Finally, we looked into the detail of JWH133, an agonist of cannabinoid 2-receptor (CB2) with potential as a therapy for cocaine and fentanyl overdose. All these results provide a better understanding of fentanyl and cocaine polydrug addiction and future drug abuse prevention.

Brief Report: Rates of Fentanyl Use Among Psychiatric Emergency Room Patients

“…Fentanyl overdose deaths increased significantly in the past 4 years, with more than 29 000 deaths in 2017. 9 The sharp rise of fentanyl overdose deaths is caused by many factors: first, the increasing adulteration of other illicit substances with fentanyl. 10 Second, the difficulty of differentiating fentanyl from other illicit substances.…”

“…4 Fentanyl is a synthetic mu-opioid receptor agonist, that is, 30 to 50 times more potent than heroin per mg. 8 A considerable variation in potency between fentanyl analogues has been observed. 3,8 Fentanyl has an onset of action of less than 5 minutes and a lethal dose of roughly 2 mg. 9 Fentanyl causes respiratory depression, which becomes worse when fentanyl is mixed with other opioids, benzodiazepines, or alcohol. 10 Evidence suggests that most fentanyl exposure among illicit substance users is unintentional.…”

Virus-CKB: an integrated bioinformatics platform and analysis resource for COVID-19 research

“…The Virus-CKB server is an integrated web server that combines our established tools and algorithms (HTDocking [ 18–22 ], TargetHunter [ 23 ], blood–brain barrier (BBB) predictor [ 20–22 ] and Spider Plot [ 18 , 19 , 24 ]) and other third-party software (Open Babel [ 25 ], JSME Molecular Editor [ 26 ], idock [ 27 ] and NGL Viewer [ 28 ]) for target identification and network systems pharmacology analysis. The Virus-CKB pipeline is shown in Figure 1 .…”

“…Virus-CKB was equipped with HTDocking [ 18–22 ], an online high-throughput molecular docking technique, for the identification of possible interactions between target proteins and the user-inputted compound(s). Up to three different conformations with the highest resolutions for each viral-related protein were cleaned and collected in Virus-CKB, depending on the availability of PDB files.…”

“…CSP-Target Mapping or Spider Plot [ 18 , 19 , 24 ] is also integrated into Virus-CKB for visualizing the molecule–protein interaction network based on the output of HTDocking and TargetHunter. The detailed information related to Spider Plot can found in our recent publication [ 24 ].…”