Structure Driven Design of Novel Human Ether-A-Go-Go-Related-Gene Channel (hERG1) Activators

Abstract

One of the main culprits in modern drug discovery is apparent cardiotoxicity of many lead-candidates via inadvertent pharmacologic blockade of K+, Ca2+ and Na+ currents. Many drugs inadvertently block hERG1 leading to an acquired form of the Long QT syndrome and potentially lethal polymorphic ventricular tachycardia. An emerging strategy is to rely on interventions with a drug that may proactively activate hERG1 channels reducing cardiovascular risks. Small molecules-activators have a great potential for co-therapies where the risk of hERG-related QT prolongation is significant and rehabilitation of the drug is impractical. Although a number of hERG1 activators have been identified in the last decade, their binding sites, functional moieties responsible for channel activation and thus mechanism of action, have yet to be established. Here, we present a proof-of-principle study that combines de-novo drug design, molecular modeling, chemical synthesis with whole cell electrophysiology and Action Potential (AP) recordings in fetal mouse ventricular myocytes to establish basic chemical principles required for efficient activator of hERG1 channel. In order to minimize the likelihood that these molecules would also block the hERG1 channel they were computationally engineered to minimize interactions with known intra-cavitary drug binding sites. The combination of experimental and theoretical studies led to identification of functional elements (functional groups, flexibility) underlying efficiency of hERG1 activators targeting binding pocket located in the S4–S5 linker, as well as identified potential side-effects in this promising line of drugs, which was associated with multi-channel targeting of the developed drugs.

A computational modelling approach combined with cellular electrophysiology data provides insights into the therapeutic benefit of targeting the late Na+ current

“…First, it is important to state that we have not developed a detailed model of a hERG activator, rather we used a simplified approach by increasing the maximal conductance of the channel. Because individual I Kr activators have specific and distinct kinetic interactions with the channel, we may predict different effects by simulating specific activators (Casis et al 2006;Guo et al 2014). For example, many I Kr activators that reduce inactivation would be expected to augment the steep current increase during the plateau phase of the action potential and perform more similarly to GS-458967 than we predict in this study.…”

“…; Guo et al . ). For example, many I Kr activators that reduce inactivation would be expected to augment the steep current increase during the plateau phase of the action potential and perform more similarly to GS‐458967 than we predict in this study.…”

Molecular Basis of Altered hERG1 Channel Gating Induced by Ginsenoside Rg3

“…Ginsenoside Rg3 is a large steroid glycoside that slows the rate of deactivation and shifts the voltage dependence of hERG1 channel activation to more negative potentials (Choi et al, 2011a;. These effects are similar to a few other hERG1 activators, including mallotoxin (Zeng et al, 2006) and NS1643 [1,3-bis(2-hydroxy-5-trifluoromethylphenyl)urea] (Xu et al, 2008) and related analogs (Guo et al, 2014). However, unlike these other compounds the onset of Rg3 activity upon extracellular application to cells is extremely rapid, suggesting that it likely binds to an extracellular accessible site on the hERG1 channel.…”

In silicoinvestigation of PARP-1 catalytic domains inholoandapostates for the design of high-affinity PARP-1 inhibitors

“…They were docked into the central cavities of previously generated and validated human ether-a go-go related gene (hERG1) K-channel models by our group [12][13][14][15][16][17][18][19] . Table 2 shows the Glide/XP docking scores of these drugs in hERG1.…”

“…It is well established that human ether-à-go-go related gene 1 (hERG1) K channel is overexpressed in many tumors and, therefore, pro-arrhythmic potential of all novel inhibitors is an important concern in structure driven drug development. To circumvent potential risks associated with druginduced QT prolongation, we report on an in silico cardiotoxicity screening against previously developed hERG1 models [12][13][14][15][16][17][18][19] by our group.…”