Chemogenomics knowledgebase and systems pharmacology for hallucinogen target identification—Salvinorin A as a case study

Abstract

Drug abuse is a serious problem worldwide. Recently, hallucinogens have been reported as a potential preventative and auxiliary therapy for substance abuse. However, the use of hallucinogens as a drug abuse treatment has potential risks, as the fundamental mechanisms of hallucinogens are not clear. So far, no scientific database is available for the mechanism research of hallucinogens. We constructed a hallucinogen-specific chemogenomics database by collecting chemicals, protein targets and pathways closely related to hallucinogens. This information, together with our established computational chemogenomics tools, such as TargetHunter and HTDocking, provided a one-step solution for the mechanism study of hallucinogens. We chose salvinorin A, a potent hallucinogen extracted from the plant Salvia divinorum, as an example to demonstrate the usability of our platform. With the help of HTDocking program, we predicted four novel targets for salvinorin A, including muscarinic acetylcholine receptor 2, cannabinoid receptor 1, cannabinoid receptor 2 and dopamine receptor 2. We looked into the interactions between salvinorin A and the predicted targets. The binding modes, pose and docking scores indicate that salvinorin A may interact with some of these predicted targets. Overall, our database enriched the information of systems pharmacological analysis, target identification and drug discovery for hallucinogens.

Salvinorin A Does Not Affect Seizure Threshold in Mice

“…Moreover, salvinorin A was reported to have significant affinity for the dopamine D2 receptor [36], which is in contrast to a previous report [5]. Computational studies revealed that not only κ opioid receptor, but also muscarinic acetylcholine receptor 2, cannabinoid CB1 and CB2 receptors, and the aforementioned D2 receptor, may represent potential molecular targets for salvinorin A [37]. Given the above, the differential effects of salvinorin A and standard κ-opioid receptor agonists on seizure susceptibility may result from the fact that the mechanism of action of salvinorin A may be more complex than was thought and is not limited to the activation of the κ-opioid receptors.…”

Structural insight into the serotonin (5-HT) receptor family by molecular docking, molecular dynamics simulation and systems pharmacology analysis

“…Hallucinogen-specific chemogenomics knowledgebase and systems pharmacology analysis We constructed a hallucinogen-specific chemogenomics database [51] that can be used for target, off-target, additional identification, and systems pharmacology analysis of small molecules and their potential targets. Several in-house chemoinformatics tools were utilized, including TargetHunter, HTDocking, and the blood-brain barrier (BBB) predictor [52,53].…”

The efficacy and safety of cilostazol as an alternative to aspirin in Chinese patients with aspirin intolerance after coronary stent implantation: a combined clinical study and computational system pharmacology analysis

“…We have constructed a cardiovascular disease (CVD)-specific chemogenomics database [19] that can be used for target/offtarget (or additional) identification and network system pharmacology analysis of small molecules and their potential targets. Several in-house chemoinformatics tools were also used, including TargetHunter, HTDocking, Blood−Brain Barrier (BBB) Predictor (developed by Xie's laboratory, Pittsburgh, PA, USA), etc [20][21][22][23][24][25][26] . CVDPlatform (www.cbligand.org/CVD) archived 984 CVD-related target proteins, 924 approved CVD drugs in clinical trials, 2080 active chemical compounds associated with the therapeutic targets of CVD, 276 cardiovascularrelated pathways, and 350 765 references.…”