Grantee Research Project Results

2006 Progress Report: Cheminformatics Tools for Toxicant Characterization

EPA Grant Number: R832721C004
Subproject: this is subproject number 004 , established and managed by the Center Director under grant R832721
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: New Jersey Research Center for Environmental Bioinformatics and Computational Toxicology
Center Director: Welsh, William J.
Title: Cheminformatics Tools for Toxicant Characterization
Investigators: Welsh, William J.
Current Investigators: Welsh, William J. , Georgopoulos, Panos G. , Floudas, Christodoulos , Rabitz, Herschel , Androulakis, Ioannis , Ierapetritou, Marianthi , Tong, Weida
Institution: University of Medicine and Dentistry of New Jersey
Current Institution: University of Medicine and Dentistry of New Jersey , Princeton University , Rutgers , U.S. Food and Drug Administration
EPA Project Officer: Hahn, Intaek
Project Period: October 1, 2005 through September 30, 2010
Project Period Covered by this Report: October 1, 2005 through September 30, 2006
RFA: Computational Toxicology: Environmental Bioinformatics Research Center (2004) RFA Text |  Recipients Lists
Research Category: Computational Toxicology , Human Health , Safer Chemicals

Objective:

The aims of the project have not changed from the original application; original objectives for the report period have been met.

Progress Summary:

The major focus during the report period was on the further development of the Shape Signatures tool for applications relevant to computational toxicology. In this regard, three major accomplishments have been achieved during this period:

• Development of a prototype version of the Shape Signatures database of Protein Data Bank (PDB)-extracted ligands;

• Development and testing of algorithms for clustering chemicals based on their shape-based features as described by their shape signatures

• Application of a computational screening procedure that identified previously unknown estrogenic compounds in a vendor-available database of chemicals.

Results to Date

The Shape Signatures computational tool co-developed in our laboratory is being refined and adapted to applications in computational toxicology. The method shows promise for screening and prioritizing potential toxicants, either as a stand-alone tool or incorporated within a hierarchical screening framework. Specifically, we have developed a prototype version of the Shape Signatures database of PDB-extracted ligands that contains ~5000 ligands extracted from all high-quality crystal structures in the publicly available P D B ( http://www.rcsb.org/pdb). The extracted ligands have been sorted alphabetically according to species (human, rat, rabbit, etc.) and protein family (kinase, protease, nuclear receptor, etc.), and each entry is hot-linked to its parent protein in the PDB. This unique Shape Signatures database is expected to have broad utility, including for the scientific community engaged in ecological and human risk assessment.

We are also adapting clustering algorithms for classifying chemicals based on their shape signature. Preliminary studies indicate that this Shape Signatures-based clustering method will offer utility for identification of potential toxicants.

Finally, we have implemented shape signatures within a multi-step screening procedure to identify previously unrecognized antiestrogenic chemicals. One study, recently published in Chemical Research in Toxicology, demonstrates the utility of this screening procedure for this and related applications in predictive toxicology and virtual screening.

Future Activities:

• Continued development of the Shape Signatures method is planed.  This effort will include further development of the Shape Signatures database of PDB-extracted ligands and of the clustering algorithm.

• In addition, we plan to develop and implement a conformer generator and a W eb-accessible interface for the Shape Signatures tool.

Journal Articles on this Report : 1 Displayed | Download in RIS Format

Publications Views

Other subproject views:	All 8 publications	2 publications in selected types	All 1 journal articles
Other center views:	All 330 publications	132 publications in selected types	All 118 journal articles

Publications

Type	Citation	Sub Project	Document Sources
Journal Article	Wang CY, Ai N, Arora S, Erenrich E, Nagarajan K, Zauhar R, Young D, Welsh WJ. Identification of previously unrecognized antiestrogenic chemicals using a novel virtual screening approach. Chemical Research in Toxicology 2006;19(12):1595-1601.	R832721C004 (2006) R832721C004 (2007)	not available

Supplemental Keywords:

computational toxicology, toxicogenomics, bioinformatics, toxicoinformatics, proteomics, metabonomics, physiomics, cytomics, genomics, transcriptomics, enviroinformatics, cheminformatics, biologically based dose-response modeling, cross-species extrapolation, risk assessment,, Health, Scientific Discipline, ENVIRONMENTAL MANAGEMENT, Risk Assessments, Biology, Biochemistry, Risk Assessment, ecological risk assessment, environmental risks, human exposure, chemical composition, risk, bioinformatics, biopollution, toxicology, human health risk, toxicologic assessment, computational toxicology, biochemical research

Relevant Websites:

http://ebctc.org Exit

Progress and Final Reports:

Original Abstract

2007 Progress Report

2008

2009

Final

Main Center Abstract and Reports:

R832721    New Jersey Research Center for Environmental Bioinformatics and Computational Toxicology

Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R832721C001 Development and Application of the DORIAN (Dose-Response Information Analysis) System
R832721C002 Hepatocyte Metabolism Model for Xenobiotics
R832721C003 Development of Computational Tools for Optimal Identification of Biological Networks
R832721C004 Cheminformatics Tools for Toxicant Characterization
R832721C005 Optimization Tools for In Silico Structural Proteomics