In Silico ADME, Metabolism Prediction and Hydrolysis Study of Melatonin Derivatives

Melatonin (MLT) is a well-known pineal hormone possessed with remarkable biological activities. However, its low oral bioavailability and high first-pass metabolism rate are important pharmacokinetics problems. Therefore, 5 MLT derivatives (1-5) were designed and synthesised in our group to solve these problems. In this work, in silico analysis of all synthetic derivatives for pharmacokinetic and drug-likeness parameters were predicted by SwissADME software. The results revealed that all derivatives (1-5) met the requirements for ideal oral bioavailability and CNS drugs. The molecular docking showed that the acetyl-MLT derivative (1) and the un-substitution at N1-position derivative 5 would be substrates of CYP1A2, while the lipophilic substituted N1-position derivatives 2-4 could not be metabolised by CYP1A2. Moreover, all N-amide derivatives (1-4) were hydrolysed and released less than 2.33% MLT after 4-hour incubation in 80% human plasma. It seemed that these derivatives preferred to behave like drugs rather than prodrugs of MLT. These findings confirmed that the addition of bulky groups at the N1-position of the MLT core could prolong the half-life, increase drug absorption and penetrate the blood brain barrier into the CNS.