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

• Published in: Acta pharmacologica Sinica Vol. 40; no. 9; pp. 1138 - 1156
• Main Authors: Wang, Yuan-qiang, Lin, Wei-wei, Wu, Nan, Wang, Si-yi, Chen, Mao-zi, Lin, Zhi-hua, Xie, Xiang-Qun, Feng, Zhi-wei
• Format: Journal Article
• Language: English
• Published: Singapore Springer Singapore 01-09-2019; Nature Publishing Group; Nature Publishing Group UK
• Subjects: Anxiety; Binding Sites; Biomedical and Life Sciences; Biomedicine; Blood-brain barrier; Chemogenomics; Cognition; Computational neuroscience; Computer simulation; Drug abuse; Drug addiction; Drug development; Humans; Immunology; Internal Medicine; Knowledge bases (artificial intelligence); Ligands; Medical Microbiology; Metabolism; Molecular Docking Simulation; Molecular dynamics; Molecular Dynamics Simulation; Mood; Pharmacology; Pharmacology - methods; Pharmacology/Toxicology; Receptors, Serotonin - chemistry; Receptors, Serotonin - metabolism; Residues; Serotonin; Serotonin Antagonists - chemistry; Serotonin Antagonists - metabolism; Serotonin Receptor Agonists - chemistry; Serotonin Receptor Agonists - metabolism; Serotonin receptors; Serotonin S1 receptors; Serotonin S2 receptors; Serotonin S5 receptors; Serotonin S7 receptors; Sleep; Thermoregulation; Vaccine; off-target prediction; molecular docking; drug abuse and addiction; molecular dynamics simulation; 5-HT receptor; drug selectivity; systems pharmacology analysis; Captagon
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-019-0217-9

Serotonin (5-HT) receptors are proteins involved in various neurological and biological processes, such as aggression, anxiety, appetite, cognition, learning, memory, mood, sleep, and thermoregulation. They are commonly associated with drug abuse and addiction due to their importance as targets for various pharmaceutical and recreational drugs. However, due to a high sequence similarity/identity among 5-HT receptors and the unavailability of the 3D structure of the different 5-HT receptor, no report was available so far regarding the systematical comparison of the key and selective residues involved in the binding pocket, making it difficult to design subtype-selective serotonergic drugs. In this work, we first built and validated three-dimensional models for all 5-HT receptors based on the existing crystal structures of 5-HT
1B
, 5-HT
2B
, and 5-HT
2C
. Then, we performed molecular docking studies between 5-HT receptors agonists/inhibitors and our 3D models. The results from docking were consistent with the known binding affinities of each model. Sequentially, we compared the binding pose and selective residues among 5-HT receptors. Our results showed that the affinity variation could be potentially attributed to the selective residues located in the binding pockets. Moreover, we performed MD simulations for 12 5-HT receptors complexed with ligands; the results were consistent with our docking results and the reported data. Finally, we carried out off-target prediction and blood–brain barrier (BBB) prediction for Captagon using our established hallucinogen-related chemogenomics knowledgebase and in-house computational tools, with the hope to provide more information regarding the use of Captagon. We showed that 5-HT
2C
, 5-HT
5A
, and 5-HT
7
were the most promising targets for Captagon before metabolism. Overall, our findings can provide insights into future drug discovery and design of medications with high specificity to the individual 5-HT receptor to decrease the risk of addiction and prevent drug abuse.