In Silico ADME, Metabolism Prediction and Hydrolysis Study of Melatonin Derivatives. (December 2020)

• Record Type: Journal Article
• Authors: Panyatip, Panyada; Nunthaboot, Nadtanet; Puthongking, Ploenthip
• Is Part Of: International journal of tryptophan research. Volume 13(2020)
• Publication Date: 2020-12
• Subjects: Melatonin -- N-amide derivative -- metabolism -- ADME -- molecular docking; Biochemistry -- Periodicals; Tryptophan -- Periodicals; Tryptophan; Biochemical Phenomena; Biochemistry; Tryptophan; Electronic journals; Periodicals; Periodicals; 572.65
• DOI: 10.1177/1178646920978245
• Languages: English
• ISSNs: 1178-6469

Abstract

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 derivative5 would be substrates of CYP1A2, while the lipophilic substituted N1 -position derivatives2 -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.