## Endpoint to Predict
- Endpoint scope: assay
- Measurement type: Ki
- Label type: continuous
- Binary semantics: pchembl
- Assay description: BACE-1 Ki Assay (BACE-1 HTRF FRET Assay): The following reagents were used in this assay. Na+-Acetate pH 5; 1% Brij-35; Glycerol; Dimethyl Sulfoxide (DMSO); Recombinant human soluble BACE-1 catalytic domain (>95% pure); APP Swedish mutant peptide substrate (QSY7-APPswe-Eu): QSY7-EISEVNLDAEFC-Europium-amide.A homogeneous time-resolved FRET assay can be used to determine IC50 values for inhibitors of the soluble human BACE-1 catalytic domain. This assay monitors the increase of 620 nm fluorescence that resulted from BACE-1 cleavage of an APPswedish APPswe mutant peptide FRET substrate (QSY7-EISEVNLDAEFC-Europium-amide). This substrate contains an N-terminal QSY7 moiety that serves as a quencher of the C-terminal Europium fluorophore (620 nm Em). In the absence of enzyme activity, 620 nm fluorescence is low in the assay and increased linearly over 3 hours in the presence of uninhibited BACE-1 enzyme. Inhibition of BACE-1 cleavage of the QSY7-APPswe-Eu substrate by inhibitors is manifested as a suppression of 620 nm fluorescence.Varying concentrations of inhibitors at 3× the final desired concentration in a volume of 10 ul are preincubated with purified human BACE-1 catalytic domain (3 nM in 10 μl) for 30 minutes at 30° C. in reaction buffer containing 20 mM Na-Acetate pH 5, 10% glycerol, 0.1% Brij-35 and 7.5% DSMO. Reactions are initiated by addition of 10 μl of 600 nM QSY7-APPswe-Eu substrate (200 nM final) to give a final reaction volume of 30 μl in a 384 well Nunc HTRF plate. The reactions are incubated at 30° C. for 1.5 hours. The 620 nm fluorescence is then read on a Rubystar HTRF plate reader (BMG Labtechnologies) using a 50 milisecond delay followed by a 400 millisecond acquisition time window. Inhibitor IC50 values are derived from non-linear regression analysis of concentration response curves. Ki values are then calculated from IC50 values using the Cheng-Prusoff equation using a previously determined μm value of 8 μM for the QSY7-APPswe-Eu substrate at BACE-1.
- Assay organism: Homo sapiens
- Target name: Beta-secretase 1
- Target type: SINGLE PROTEIN
- Target organism: Homo sapiens

## Reference Molecule A
- Canonical SMILES: COc1cnc2c(Nc3ccc(F)c([C@]4(C)CS(=O)(=O)N(C)C(=N)N4)c3)ncnc2c1
- Properties:
- ChEMBL ID: CHEMBL5971642
- Molecular weight: 445.48
- Heavy atoms: 31
- Hydrogen bond donors: 3
- Hydrogen bond acceptors: 8
- TPSA: 133.19
- LogP: 1.93
- Rotatable bonds: 4
- Ring count: 4
- Aromatic rings: 3
- Formal charge: 0
- Fraction Csp3: 0.26
- QED: 0.55

## Known Reference Result on This Endpoint
- Molecule A clean result: median pChEMBL = 8.37
- This result is provided as context for predicting Molecule B on the same endpoint.

## Reference Molecule A Other ChEMBL Evidence
- type Ki; relation =; value 4.3; units nM; pChEMBL 8.37; comment 525150
- type Ki; relation =; value 4.3; units nM; pChEMBL 8.37; comment 525171

## Query Molecule B
- Canonical SMILES: COc1cccnc1Nc1ccnc([C@]2(C)CS(=O)(=O)N(C)C(=N)N2)c1
- Properties:
- ChEMBL ID: CHEMBL5866388
- Molecular weight: 376.44
- Heavy atoms: 26
- Hydrogen bond donors: 3
- Hydrogen bond acceptors: 7
- TPSA: 120.3
- LogP: 1.24
- Rotatable bonds: 4
- Ring count: 3
- Aromatic rings: 2
- Formal charge: 0
- Fraction Csp3: 0.31
- QED: 0.73

## Molecule Similarity
- Weighted Tanimoto: 0.48

Answer: 6.46