2020-05-01

Updates

Release 2020.05.01

AMED cardiotoxicity database release 2020.05.01 contains updates to expand the coverage of inhibition data to all human ion channels related to heat rate. The ion channels were obtained from UniProt as human ion channels for which GO:0086091 (regulation of heart rate by cardiac conduction) or GO:0002027 (regulation of heart rate) were assigned. Then inhibitory activities assigned to the ion channels were extracted from ChMEBL (v25), and merged to those for hERG, Nav1.5, Kv1.5, and Cav1.2 already registered in the previous release 2020.04.02. Table 1 shows the list of the targets and the number of assay results/compounds registered in AMED cardiotoxicity database release 2020.05.01.

Table 1

Target	Target type	The number of assays	The number of compounds
CAB2	SINGLE PROTEIN	1	1
CACNA2D1	SINGLE PROTEIN	164	156
Cav1.2	SINGLE PROTEIN	578	427
Cav1.3	SINGLE PROTEIN	36	29
Cav3.1	SINGLE PROTEIN	1,146	746
HCN4	SINGLE PROTEIN	66	51
hERG	SINGLE PROTEIN	345,280	324,114
hTRPM4	SINGLE PROTEIN	1	1
KCNE1(MinK)	SINGLE PROTEIN	9	9
Kir2.1	SINGLE PROTEIN	19	19
Kv1.5	SINGLE PROTEIN	1,387	1,086
Kv4.3	SINGLE PROTEIN	76	68
Kv7.1	SINGLE PROTEIN	109	73
Nav1.5	SINGLE PROTEIN	2,860	2,233
Nav1.8	SINGLE PROTEIN	315	227
Ryanodine receptor 2	SINGLE PROTEIN	63	53
Sodium channel alpha subunit	PROTEIN FAMILY	16	16
Voltage-gated L-type calcium channel	PROTEIN FAMILY	290	215
Voltage-gated potassium channel	PROTEIN FAMILY	19	19
Voltage-gated calcium channel	PROTEIN COMPLEX GROUP	51	49
CACNA2D1/Cav2.2/CAB3	PROTEIN COMPLEX	2	1
Cav1.2/CACNA2D1/CAB1	PROTEIN COMPLEX	64	49
Cav2.1/CACNA2D1/CAB1	PROTEIN COMPLEX	6	6
KChIP2/Kv4.3	PROTEIN COMPLEX	4	4
Kir3.1/Kir3.2	PROTEIN COMPLEX	249	121
Kir3.1/Kir3.4	PROTEIN COMPLEX	324	177
Kv7.1/KCNE1(MinK)	PROTEIN COMPLEX	175	133
Kv7.1/Misshapen-like kinase 1	PROTEIN COMPLEX	3	3

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2020-04-02

Updates

Release 2020.04.02

AMED cardiotoxicity database release 2020.04.02 contains following updates about data and prediction models. Detailed description about each update/function were to be available soon.

Update of database

1. Inclusion of activity information about other ion channels related to cardiotoxicity (Nav1.5, Kv1.5, and Cav1.2) along with hERG.

2. Update following those in public database.

• ChEMBL (→v.24)
• NCGC (→v2.1)

3. Additional assay results measured in AMED Development of a Drug Discovery Informatics System project by RIKEN and sourcing to Eurofins (hERG) and Icagen. (Nav1.5, Kv1.5, and Cav1.2)

Additional functions

1. Updated hERG discrimination model

• New model corresponding to database update
• Assessment of applicability domain based on molecular similarity to learning data
• Output values are now scaled as probability from 0 to 1
• Change of SVM implementation from SVM^light to scikit-learn.svm.svc

2. New prediction models

• hERG regression model (implemented using scikit-learn.svm.svr)
• Nav1.5 discrimination/regression model (implemented using tensorflow.keras) with pre-learning of other sodium channels
• Kv1.5 discrimination model (implemented using tensorflow.keras) with pre-learning of other potassium channels
• Cav1.2 discrimination model (implemented using tensorflow.keras) with pre-learning of other calcium channels

3. Downloads of search/prediction results

• Search/prediction results can be download by clicking "download" button in the results page.
• Due to the calculation cost, sdf input for prediction was limited up to 100 compounds in a single run.
• Direct download of the whole database was removed due to the large data size and ongoing collaboration with a software company. When license and usage conditions are sorted, we intend to prepare application form for the data download.


2019-11-05

AMED Cardiotoxicity Database is a database of small molecules which bind to various ion channels and potentially cause cardiotoxic risk.

AMED Cardiotoxicity Database compiles cardiotoxicity-related information from publicly available databases and integrates them in standardized format. As an initial target, bioactivities for hERG potassium channel were collected from ChEMBL, NIH Chemical Genomics Center, and hERGCentral because the inhibition of hERG potassium channel is closely related to the prolonged QT interval, and to assess the risk could greatly contribute to avoid delay of the development of therapeutic compounds or withdrawal of marketed drugs.

Data sources

1. ChEMBL

ChEMBL is a bioactivity database maintained by European Bioinformatics Institute, and frequently used in various cheminformatics researches as the de facto standard database. According to the target ID (CHEMBL240) of hERG, 2,153 hERG-related bioassays were registered in ChEMBL version 22, then, 10,976 activity entries for the assays were extracted. To ensure validity of the data, entries with low confidence value, undesirable data validity comments, or specified as potential duplicate were excluded. hERG-related assays which did not measure inhibitory activities were manually removed by checking assay descriptions.

2. NIH Chemical Genomics Center (NCGC)

Quantitative high throughput screening to determine in vitro hERG channel blockage by NCGC was derived from PubChem bioassays (AID = 588834). The data related to hERG (about 2,688 compounds) in LOPAC1280 library (Sigma) were determined by FluxORTM thallium flux assay. The data contain both EC50 values for both hERG inhibitors and activators along with some undefined data because the EC50 values were calculated from automated sigmoid curve-fitting to dose response of hERG activities by Hill equation, and did not distinguish the positive and negative values of Hill coefficient (inhibitor/activator) or fitting quality (inconclusive entries). Some results in this dataset were redundantly included in ChEMBL database. However, the outcome comments attached to the entries to specify whether EC50 values means inhibitors, activators, and inconclusive ones were omitted in ChEMBL. Thus, the corresponding entries were excluded from the ChEMBL dataset. In the NCGC dataset, hERG inhibitors were defined as the entries with both outcome comments specifying "inhibitor" and sufficient inhibitory activity (EC50<10µM in this case). Compounds with EC50 exceeding 10µM and compounds specified as activators and inconclusive entries were defined as negative compounds.

3. hERGCentral

hERGCentral is a database containing hERG activity information of more than 300,000 compounds. Because hERGCentral database (www.hergcentral.org) is currently out of order, values of the percent inhibitory activities of 318,496 compounds at 10µM concentration determined by IonWorks Quattro (MDC, Sunnyvale, CA) in population patch clamp (PPC) mode were retrieved from supporting information of manuscript about statistical analysis of hERGCentral dataset published by Fang et. al.(2015).

The number of compounds

AMED cardiotoxity database consists of 9,259 hERG inhibitors (IC50≤10µM) and 279,718 inactive compounds (IC50>10µM). The assessment of structural diversity using Murcko frameworks revealed that the database contains more than 2 times as many scaffold for hERG inhibitors as any of the existing databases, and covering 18.0% of all chemical space occupied by whole compounds in ChEMBL (438,551 frameworks).

database	class	Number of compounds	Number of Murcko frameworks
ChEMBL	Inhibitors	4,793	2,474
	Inactives	5,275	3,012
	All	10,068	4,954
NCGC	Inhibitors	232	173
	Inactives	1,234	504
	All	1,466	639
hERGCentral	Inhibitors	4,321	2,708
	Inactives	274,536	73,419
	All	278,857	74,687
AMED cardiotoxity database	Inhibitors	9,259	5,203
	Inactives	279,718	75,868
	All	288,977	79,014

Reference

Sato T, Yuki H, Ogura K, Honma T Construction of an integrated database for hERG blocking small molecules.
PLOS ONE 13(7) (2018): e0199348. https://doi.org/10.1371/journal.pone.0199348