Serotonin (5-HT) receptors are proteins involved in various neurological and biological processes,such as aggression,anxiety,appetite,cognition,leaing,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.