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

Authors: Yuan-qiang Wang1,2,3,4,5,6, Wei-wei Lin4,5,6, Nan Wu4,5,6, Si-yi Wang4,5,6, Mao-zi Chen4,5,6, Zhi-hua Lin1,2,3, Xiang-Qun Xie4,5,6,7, Zhi-wei Feng4,5,6
1 School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China
2 Chongqing Key Laboratory of Medicinal Chemistry and Molecular Pharmacology, Chongqing 400054, China
3 Chongqing Key Laboratory of Targeted Drug Screening and Effect Evaluation, Chongqing 400054, China
4 Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA
5 NIH National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, PA 15261, USA
6 Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
7 Departments of Computational Biology and Structural Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
Correspondence to: Xiang-Qun Xie:, Zhi-wei Feng:,
DOI: 10.1038/s41401-019-0217-9
Received: 28 September 2018
Accepted: 17 January 2019
Advance online: 27 February 2019


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-HT1B, 5-HT2B, and 5-HT2C. 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-HT2C, 5-HT5A, and 5-HT7 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.
Keywords: 5-HT receptor; molecular docking; molecular dynamics simulation; systems pharmacology analysis; off-target prediction; drug abuse and addiction; drug selectivity; Captagon

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