Newly designed melatonin analogues with potential neuroprotective effects

Catechol-O-methyltransferase (COMT) degrades catecholamine neurotransmitters, including dopamine. Thus, COMT inhibitors are of potential use in the treatment of neurodegenerative disorders associated with dopamine depletion, such as Parkinson's disease. In this work, we explored the molecular recognition between the soluble form of human COMT (S-COMT) and two newly designed melatonin analogues (dm-115 and IIcD). These derivatives present the catechol group, which makes them good candidates to interact with S-COMT. Dopamine and L-dopa were used as references to foresee the possible efficiency of dm-115 and IIcD as COMT inhibitors. The examination of the complexes revealed that Trp38, Met40, Leu198, Asp141, Trp143, Lys144, Asn170, Pro174, Glu199, Tyr200 as well as SAM cofactor and Mg2+ are important for the binding affinity of the inhibitors, generating important hydrophobic contacts. These models allowed to further determine the electrostatic and non-electrostatic contributions to the binding free energy (Delta G(b)). The presented results confirm that binding energies were more favorable for the 108 V S-COMT system compared to 108 M S-COMT. They also suggest that the binding energy between COMT and dm-115 is similar to that of the L-dopa and slightly higher than that of dopamine. These findings shed light on the importance of melatonin analogues in the context of neuroprotection and strongly suggest that they may act as COMT inhibitors, in addition to their protective effects against oxidative stress.

Automated summary

This study explored the molecular recognition between human COMT and two newly designed melatonin analogues, suggesting that these analogues may act as COMT inhibitors. The analysis of binding energies revealed that the binding energy between COMT and dm-115 is similar to that of L-dopa and slightly higher than that of dopamine.