100
P. Gong et al.
developed a novel in silico toxicology approach that is based on molecular modeling
and guided by mode of action (MoA). Our approach is implemented through a targetspecific toxicity knowledgebase (TsTKb), consisting of a pre-categorized database
of chemical MoA (ChemMoA) and a series of pre-built, category-specific classification and quantification models. ChemMoA serves as the depository of chemicals with
known MoAs or molecular initiating events (i.e., known target biomacromolecules)
and quantitative information for measured toxicity endpoints (if available). The models allow a user to qualitatively classify an uncharacterized chemical by MoA and
quantitatively predict its toxicity potency. This approach is currently under development and will evolve to incorporate physiologically based pharmacokinetic (PBPK)
modeling to address absorption, distribution, metabolism and excretion (ADME)
processes in a biological system. The fully developed approach is believed to significantly advance in silico-based predictive toxicology and provide a new powerful
toolbox for regulators, the chemical industry and the relevant academic communities.
Keywords Mode of action (MoA) · Molecular dynamics (MD) simulation ·
Molecular docking · Deep learning · Predictive toxicology · Target-specific
toxicity knowledgebase (TsTKb) · Chemical mode of action database
(ChemMoA) · Qualitative classification · Quantitative prediction · Quantitative
structure–activity relationship (QSAR)
Abbreviations
3D
Three-dimensional
3Rs
Refine, reduce, and replace
ACToR
Aggregated Computational Toxicology Online Resource
ADME
Absorption, distribution, metabolism, and excretion
AOP
Adverse outcome pathway
BLAST
Basic local alignment search tool
BPA
Bisphenol A
ChemMoA Chemical MoA
DSSTox
Distributed Structure-Searchable Toxicity
dyPLID
Dynamic protein–ligand interaction descriptors
EADB
Estrogenic Activity Database
EDKB
Endocrine Disruptor Knowledge Base
EDSP
Endocrine Disruptor Screening Program
EPA
Environmental Protection Agency
EU
European Union
FDA
Food and Drug Administration
iPSC
Induced Pluripotent Stem Cell
LTKB
Liver Toxicity Knowledge Base
MD
Molecular Dynamics
MIE
Molecular Initiating Event
P. Gong et al.
developed a novel in silico toxicology approach that is based on molecular modeling
and guided by mode of action (MoA). Our approach is implemented through a targetspecific toxicity knowledgebase (TsTKb), consisting of a pre-categorized database
of chemical MoA (ChemMoA) and a series of pre-built, category-specific classification and quantification models. ChemMoA serves as the depository of chemicals with
known MoAs or molecular initiating events (i.e., known target biomacromolecules)
and quantitative information for measured toxicity endpoints (if available). The models allow a user to qualitatively classify an uncharacterized chemical by MoA and
quantitatively predict its toxicity potency. This approach is currently under development and will evolve to incorporate physiologically based pharmacokinetic (PBPK)
modeling to address absorption, distribution, metabolism and excretion (ADME)
processes in a biological system. The fully developed approach is believed to significantly advance in silico-based predictive toxicology and provide a new powerful
toolbox for regulators, the chemical industry and the relevant academic communities.
Keywords Mode of action (MoA) · Molecular dynamics (MD) simulation ·
Molecular docking · Deep learning · Predictive toxicology · Target-specific
toxicity knowledgebase (TsTKb) · Chemical mode of action database
(ChemMoA) · Qualitative classification · Quantitative prediction · Quantitative
structure–activity relationship (QSAR)
Abbreviations
3D
Three-dimensional
3Rs
Refine, reduce, and replace
ACToR
Aggregated Computational Toxicology Online Resource
ADME
Absorption, distribution, metabolism, and excretion
AOP
Adverse outcome pathway
BLAST
Basic local alignment search tool
BPA
Bisphenol A
ChemMoA Chemical MoA
DSSTox
Distributed Structure-Searchable Toxicity
dyPLID
Dynamic protein–ligand interaction descriptors
EADB
Estrogenic Activity Database
EDKB
Endocrine Disruptor Knowledge Base
EDSP
Endocrine Disruptor Screening Program
EPA
Environmental Protection Agency
EU
European Union
FDA
Food and Drug Administration
iPSC
Induced Pluripotent Stem Cell
LTKB
Liver Toxicity Knowledge Base
MD
Molecular Dynamics
MIE
Molecular Initiating Event