Molecular Dynamics Insights into Interactions Between Caffeine and 5-Hydroxytryptophan (Serotonin) in Water and Ethyl Lactate

S Shyam and M Sharma, CHEMISTRYSELECT, 10, e202500412 (2025).

DOI: 10.1002/slct.202500412

Caffeine is found in food and beverages and is also a pharmaceutically relevant drug, which is used as an analgesic adjuvant. Serotonin is mainly found in the gastrointestinal tract and central nervous system of living beings and is also used as a supplement to regulate mood. The molecular dynamics simulation results show that serotonin acts as an anti-hydrotrope and enhances the aggregation of caffeine and serotonin in water. On the other hand, both caffeine and serotonin form solvated monomers or dimers in ethyl lactate. The crystalline Form-II of caffeine consists of both antiparallel and parallel dimers of caffeine, and these types of caffeine dimers are also present in water. The DFT calculations show that water interacts favorably with the antiparallel dimers than the parallel dimers of caffeine. The serotonin enhances the percentage of parallel caffeine dimers in water, but the percentage of antiparallel caffeine dimers in the presence of serotonin is higher in ethyl lactate.

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