The role of natural products (NPs) in drug discovery cannot be disputed and has been extensively documented [1]. But surprisingly, the human Ether-`a-go-go Related Gene (hERG) channel blocking profile of NPs is often not routinely assessed. The hERG K+ plays an essential role in the normal electrical activity in the heart. Mutations in the hERG gene and hERG channel blockage by small molecules are associated with increased risk of fatal arrhythmias. Due to the notorious hERG channel ligand promiscuity, and the withdrawal of several drugs from the market due to hERG-related cardiotoxicity, this voltage-gate K+ channel has solidified as an important antitarget in early drug discovery and development. Chemical investigations of V. africana led to the isolation of a new iboga-indole alkaloid derivative: voacamine A and eight (8) known alkaloids. The structures of the compounds were established by spectroscopic analyses as well as by comparison with published data. Recently, voacangine, a major alkaloid from V. africana has been identified as a potent blocker of the hERG channel, with an IC50 of 0.30 μM in hEK293 cells. This has prompted us to assess the hERG channel related cardiotoxicity of NPs isolated from phylogenetic Voacanga species using machine learning applications. The rationale behind computer based approaches is the relatively lower cost and the time factor involved, when compared to standard experimental approaches for hERG channel assessment. We have estimated the hERG profile of ninety (90) alkaloids by calculating the predicted (loghERG). We have also established if further in vivo studies are warrantable to assess the cardiotoxicity of these hits. The predicted IC50 values for the blockage of the (hERG K+) channels (loghERG) were calculated by using the QikProp and a machine learning (ML) approach implemented in the pkCSM webserver. All the bisindole alkaloids have a greater hERG channel blocking profile than the monoterpenoids indole alkaloids due to their structural complexity. Our results showed that aromatic rings are the fundamental features of the usually recognized hERG channel blocker pharmacophore, and are associated with pi-stacking or hydrophobic interactions. Also, substituents that increase lipophilicity can increase hERG channel binding.

Chemoinformatic investigation of iboga-indole alkaloids modulating the hERG channel

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.