## Endpoint to Predict
- Endpoint scope: assay
- Measurement type: IC50
- Label type: continuous
- Binary semantics: pchembl
- Assay description: hERG Inhibition Assay: The human ether-a-go-go related gene (hERG) encodes the inward rectifying voltage gated potassium channel in the heart (IKr) which is involved in cardiac repolarisation. IKr current inhibition has been shown to elongate the cardiac action potential, a phenomenon associated with increased risk of arrhythmia. IKr current inhibition accounts for the vast majority of known cases of drug-induced QT-prolongation. A number of drugs have been withdrawn from late stage clinical trials due to these cardiotoxic effects, therefore it is important to identify inhibitors early in drug discovery.The hERG inhibition study aims at quantifying the in vitro effects of compounds of the invention on the potassium-selective IKr current generated in normoxic conditions in stably transfected HEK 293 cells with the human ether-a-go-go-related gene (hERG).Whole-cell currents (acquisition by manual patch-clamp) elicited during a voltage pulse were recorded in baseline conditions and following application of tested compounds (5 minutes of exposure). The concentrations of tested compounds (0.3 μM; 3 μM; 10 μM; 30 μM) reflect a range believed to exceed the concentrations at expected efficacy doses in preclinical models.The pulses protocol applied is described as follow: the holding potential (every 3 seconds) was stepped from −80 mV to a maximum value of +40 mV, starting with −40 mV, in eight increments of +10 mV, for a period of 1 second. The membrane potential was then returned to −55 mV, after each of these incremented steps, for 1 second and finally repolarized to −80 mV for 1 second.The current density recorded were normalized against the baseline conditions and corrected for solvent effect and time-dependent current run-down using experimental design in test compound free conditions.Inhibition curves were obtained for compounds and the concentrations which decreased 50% of the current density determined in the baseline conditions (IC50) were determined. All compounds for which the IC50 value is above 10 μM are not considered to be potent inhibitors of the hERG channel whereas compounds with IC50 values below 1 μM are considered potent hERG channel inhibitors.
- Assay organism: Homo sapiens
- Target name: Voltage-gated inwardly rectifying potassium channel KCNH2
- Target type: SINGLE PROTEIN
- Target organism: Homo sapiens

## Reference Molecule A
- Canonical SMILES: COc1cccc(C(=O)N2CCn3c(-c4nc(C)ns4)nnc3[C@H]2C)c1
- Properties:
- ChEMBL ID: CHEMBL4114258
- Molecule type: Small molecule
- Molecular weight: 370.44
- Heavy atoms: 26
- Hydrogen bond donors: 0
- Hydrogen bond acceptors: 7
- TPSA: 86.03
- LogP: 2.33
- Rotatable bonds: 3
- Ring count: 4
- Aromatic rings: 3
- Formal charge: 0
- Fraction Csp3: 0.35
- QED: 0.7

## Known Reference Result on This Endpoint
- Molecule A clean result: median pChEMBL = 4.16
- This result is provided as context for predicting Molecule B on the same endpoint.

## Reference Molecule A Other ChEMBL Evidence
- type IC50; relation =; value 70000; units nM; pChEMBL 4.16; comment 535322

## Query Molecule B
- Canonical SMILES: Cc1nsc(-c2nnc3n2CCN(C(=O)c2ccc(F)c(F)c2)[C@@H]3C)n1
- Properties:
- ChEMBL ID: CHEMBL4112037
- Molecule type: Small molecule
- Molecular weight: 376.39
- Heavy atoms: 26
- Hydrogen bond donors: 0
- Hydrogen bond acceptors: 6
- TPSA: 76.8
- LogP: 2.6
- Rotatable bonds: 2
- Ring count: 4
- Aromatic rings: 3
- Formal charge: 0
- Fraction Csp3: 0.31
- QED: 0.69

## Molecule Similarity
- Weighted Tanimoto: 0.71

Answer: 4.16