In silico interaction of Mitragynine and its analogues with human Ether-a- Go- Go- Related Gene (hERG) channel

Abstract

IntroductionThe human ether-a-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly delayed rectifier potassium channel. Blockade of this channel by a diverse group of drugs can cause long QT syndrome, which can lead to lethal cardiac arrhythmias. ObjectiveThis study aims to predict and understand the molecular interactions taking place between hERG channel with the natural compound mitragynine and its analogues, such as paynantheine, speciogynine and speciociliatine, using in silico approach.Methods: Automated docking simulations were performed inside a previously established hERG homology model. Low-energy conformations of the test compounds were docked into the possible binding site of the hERG channel and their molecular interactions and binding affinities were further analysed. Results & DiscussionBased on the free energy of binding computed using the docking software, mitragynine (–6.25 kcal mol–1), paynantheine (–6.06 kcal mol–1), speciogynine (–6.15 kcal mol–1) and speciociliatine (–6.03 kcal mol–1) were weaker hERG blockers as compared to the well-known high affinity hERG blocker, terfenadine (−7.95 kcal mol–1). The range of estimated inhibition constant, Ki, shown by mitragynine and its analogues was from 26.42 μM to 38.26 μM, which were consistently higher than terfenadine (1.49 μM). Mitragynine and paynantheine were found to form ϖ-ϖ interaction with the aromatic residue, Tyr652, located in the S6 domain of hERG channel, while speciogynine was shown to interact with the polar residue, Ser624, which is located near the base of the pore helix. On the other hand, there was no obvious interaction seen between speciociliatine and the hERG model. ConclusionOur results showed that mitragynine and its analogues were weak hERG blockers as compared with terfenadine. Tocotrienol