ChemFH

ChemFH (Chemical Frequent Hitter) is an integrated online platform for the identification of potential frequent hitters, including colloidal aggregate, firefly luciferase reporter enzyme inhibition, fluorescence, chemical reactivity and promiscuity. Based on the collection of a large and high-quality database and the application of Graph Neural Networks architectures, the prediction models implemented in ChemFH are able to achieve reliable detection capability of frequent hitters, thus improving the efficiency of drug R&D.

Calculation

Evaluation Mode

Evaluation Pattern is able to comprehensively evaluate the risk of the queried molecule based on the combination of credible prediction models and useful substructure rules.

Learn More

Screening Mode

Screening Mode is able to screen a molecular dataset and detect potential frequent hitters, thus improving the credibility of experimental results and decreasing unnecessary cost.

Learn More

Mechanism Explanation

Colloidal aggregators

Compound aggregation tends to start when the concentration is above the CAC and end as aggregators form with radius of approximately 30-600 nm. The resulting colloidal aggregators would non-specifically bind to the surface of proteins, thus inducing local protein unfolding, which usually results in destabilization or denaturation of enzymes.

FLuc inhibitors

Due to its unique catalysis mechanism, FLuc is widely used in a variety of HTS bioluminescence assays, especially in the assay which aims to study gene expression at the transcriptional level. However, the inhibition of Fluc by unexpected FLuc inhibitors would produce interference to HTS assays.

Blue/Green fluorescence

Fluorescence is the process by which a molecule, called fluorophore or fluorescent dye, absorbs a photon of light, exciting an electron to a higher energy state. Fluorophores have many applications, including as enzyme substrates, labels for biomolecules, cellular stains and environmental indicators. However, the appearance of fluorescent compound would produce interference to related HTS assays.

Reactive compounds

Chemical reactive compounds typically result in the chemical modification of reactive protein residues or, less frequently, the modification of nucleophilic assay reagents。

Promiscuous compounds

Promiscuous compounds refer to compounds that specifically bind to different macromolecular targets. These multiple interactions may include unintended targets, thus triggering adverse reactions and other safety issues.

Other assay interferences

Alpha-screen, FRET, TR-FRET, absorbance artifacts are included.

Highlights

01 High-quality and Large Database Collection

Based on the collection from related literatures and large databases, a high-quality dataset containing more than 810,000 compounds, which has been rigorously prepared by a multi-step scheme, is used for the model development and substructure compilation for frequent hitters.
02 Graph Neural Networks

Graph neural networks (GNNs) were used to process molecular graph structures, learn molecular features and develop the credible models for frequent hitters in ChemFH.
03 Multiple Mechanisms of Frequent Hitter Prediction

The predictions on representative false positive mechanisms are provided, including colloidal aggregate, firefly luciferase reporter enzyme inhibition, fluorescence, and chemical reactivity. Besides, to provide more reference about the authenticity, the prediction on promiscuity is also provided in ChemFH.
04 Representative Substructures

Based on the large and high-quality collected dataset, a total of 102 representative substructures with an averaged precision value higher than 0.85 were used for a comprehensive exploration of frequent hitters.