title: 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.
authors.affiliation: Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Jiqing
authors.initials: J
authors.lastname: Guo
authors.affiliation: Centre for Molecular Simulation, Biochemistry Research Cluster, Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada; Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, Turkey.
authors.forename: Serdar
authors.initials: S
authors.lastname: Durdagi
authors.affiliation: Department of Chemistry, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Changalov
authors.affiliation: Centre for Molecular Simulation, Biochemistry Research Cluster, Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Perissinotti
authors.affiliation: Department of Chemistry, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Hargreaves
authors.affiliation: Department of Chemistry, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Back
authors.affiliation: Centre for Molecular Simulation, Biochemistry Research Cluster, Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Sergei Y
authors.initials: SY
authors.lastname: Noskov
authors.affiliation: Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Duff
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D001665:Binding Sites; D003408:Cresols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D062313:Databases, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D054852:Small Molecule Libraries
chemical_list: D003408:Cresols; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D008024:Ligands; D010671:Phenylurea Compounds; D054852:Small Molecule Libraries; C507624:1,3-bis(2-hydroxy-5-trifluoromethylphenyl)urea