Characterizing Eckol as a Therapeutic Aid: A Systematic Review

Manandhar, Bandana; Paudel, Pradeep; Seong, Su Hui; Jung, Hyun Ah; Choi, Jae Sue

The involvement of G-protein coupled receptors in human pathophysiology and their pharmacological traceability has emphasized on design and implementation of high-throughput G protein coupled receptor functional assays to identify novel drug candidates [98] . Dopamine receptors are specific therapeutic targets for PD, schizophrenia, and drug abuse. According to the stimulatory or inhibitory properties of the secondary messenger, cyclic adenosine monophosphate, dopamine receptors are categorized as Gα s/olf -coupled D 1 -like (D 1 and D 5 ) and Gα i/o -coupled D 2 -like (D 2 , D 3 , and D 4 ) receptors [99] . At a concentration of 25 µM, eckol conferred a 10.60% and 36.55% of the control agonist effect on the human dopamine D 3 receptor (hD 3 R) and human D 4 receptor (hD 4 R), respectively. At 50 µM eckol, the agonist response increased to above 50%, giving EC 50 values of 48.62 ± 3.21 and 42.55 ± 2.54 µM for hD 3 R and hD 4 R, respectively. However, eckol did not show any modulating effect on dopamine D 1 , serotonin 1A (5-HT 1A ), vasopressin (V 1A ), tachykinin (NK 1 ) or muscarinic (M 5 ) receptors [56] . In the context of molecular docking, negative binding energy (−6.41 kcal/mol) was exhibited by eckol, bound to the active site of the hD 3 R receptor, forming five H-bond interactions. Similarly, eckol bound to the active site cavity of hD 4 R with a negative binding energy (−6.46 kcal/mol) that was lower than dopamine (−5.68 kcal/mol), possibly as a result of four H-bond interactions. Even though eckol did not form a salt bridge to the carboxylate group of Asp110 of hD 3 R and Asp115 of hD 4 R important for high-affinity ligand binding to dopaminergic receptors [100] , it formed an H-bond (O-H) interaction. Molecular dynamics (MD) simulation showed that the interaction of eckol with the binding pocket had changed significantly. Through the H-bonds, seven water molecules were involved in the interaction with eckol. In the MD simulation, Ser192 and Phe346 were the two new interacting residues. Eckol formed an H-bond interaction with Ser192 at a distance of 2.82 Å that was important for the activation of D 3 R. On the other hand, Phe346 displayed a hydrophobic interaction with eckol initiating a conformational change in the protein and ligand inside the binding pocket. Through π-π interactions, Phe346 also bound to eticlopride and dopamine contributing to the stabilization of ligand inside the binding pocket. The conserved serine residues in helix V also plays an important role as a molecular determinant for agonist-induced signaling from dopamine receptors. The Ser192 of hD 3 R (Ser197 of hD 4 R) and a hydroxyl moiety of eckol presented an H-bond interaction, implying eckol as a dual hD 3 /D 4 R agonist. A logP o/w value of 2.99, an excellent binding to plasma protein (100%) and a moderate human intestinal absorption of 55.60%, was predicted through in silico pharmacokinetic parameter PreADMET. Also, the in vivo blood-brain barrier penetration calculations showed a moderate absorption (25%) by the central nervous system. [56] .