Na+-channel modulating effect of the inotropic compound S(-)BDF 9196 in human myocardium

As chemists can easily produce large numbers of new potential drug candidates, there is growing demand for high capacity models that can help in driving the chemistry towards efficacious and safe candidates before progressing towards more complex models. Traditionally, the cardiovascular (CV) safety domain plays an important role in this process, as many preclinical CV biomarkers seem to have high prognostic value for the clinical outcome. Throughout the industry, traditional ion channel binding data are generated to drive the early selection process. Although this assay can generate data at high capacity, it has the disadvantage of producing high numbers of false negatives. Therefore, our company applies the isolated guinea pig right atrium (GPRA) assay early-on in discovery. This functional multi-channel/multi-receptor model seems much more predictive in identifying potential CV liabilities. Unfortunately however, its capacity is limited, and there is no room for full automation. We assessed the correlation between ion channel binding and the GPRA's Rate of Contraction (RC), Contractile Force (CF), and effective refractory frequency (ERF) measures assay using over six thousand different data points. Furthermore, the existing experimental knowledge base was used to develop a set of in silico classification models attempting to mimic the GPRA inhibitory activity. The Naïve Bayesian classifier was used to built several models, using the ion channel binding data or in silico computed properties and structural fingerprints as descriptors. The models were validated on an independent and diverse test set of 200 reference compounds. Performances were assessed on the bases of their overall accuracy, sensitivity and specificity in detecting both active and inactive molecules. Our data show that all in silico models are highly predictive of actual GPRA data, at a level equivalent or superior to the ion channel binding assays. Furthermore, the models were interpreted in terms of the descriptors used to highlight the undesirable areas in the explored chemical space, specifically regions of low polarity, high lipophilicity and high molecular weight. In conclusion, we developed a predictive in silico model of a complex physiological assay based on a large and high quality set of experimental data. This model allows high throughput in silico safety screening based on chemical structure within a given chemical space.

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“…Physiologically, a definite correlation between CF effects and the binding to Na ? [38][39][40] and Ca 2? [41] channels is expected.…”

Section: Resultsmentioning

confidence: 99%

Cardio-vascular safety beyond hERG: in silico modelling of a guinea pig right atrium assay

Fenu¹,

Teisman²,

Buck

et al. 2009

J Comput Aided Mol Des

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CNF and DNT

Hoffmann

Schmidt

Reviews of Physiology, Biochemistry and Pharmacology

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The actin cytoskeleton of mammalian cells is involved in many processes that affect the growth and colonization of bacteria, such as migration of immune cells, phagocytosis by macrophages, secretion of cytokines, maintenance of epithelial barrier functions and others. With respect to these functions, it is not surprising that many bacterial protein toxins, which are important virulence factors and causative agents of human and/or animal diseases, target the actin cytoskeleton of the host. Some toxins target actin directly, such as the C2 toxin produced by Clostridium botulinum. Moreover, bacterial toxins target the cytoskeleton indirectly by modifying actin regulators such as the low-molecular-mass guanosine triphosphate (GTP)-binding proteins of the Rho family. Remarkably, toxins affect these GTPases in a bidirectional manner. Some toxins inhibit and some activate the GTPases. Here we review the Rho-activating toxins CNF1 and CNF2 (cytotoxic necrotizing factors) from Escherichia coli, the Yersinia CNF(Y) and the dermonecrotic toxin (DNT) from Bordetella species. We describe and compare their uptake into mammalian cells, mode of action, structure-function relationship, substrate specificity and role in diseases.

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Current–Voltage Relationship for Late Na+ Current in Adult Rat Ventricular Myocytes

Clark

Giles

2016

Na Channels From Phyla to Function

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Na+-channel modulating effect of the inotropic compound S(-)BDF 9196 in human myocardium

Cited by 7 publications

References 25 publications

Cardio-vascular safety beyond hERG: in silico modelling of a guinea pig right atrium assay

Cardio-vascular safety beyond hERG: in silico modelling of a guinea pig right atrium assay

CNF and DNT

Current–Voltage Relationship for Late Na+ Current in Adult Rat Ventricular Myocytes

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