Notox toxicity analysis of molecules and their derivatives
Download
1 / 31

NoTox: Toxicity Analysis of Molecules and their derivatives - PowerPoint PPT Presentation


  • 563 Views
  • Uploaded on

NoTox: Toxicity Analysis of Molecules and their derivatives. Primary Advisor : Professor David J. Wild Bioinformatics Advisor: Professor Sun Kim. What is Computational Toxicology.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'NoTox: Toxicity Analysis of Molecules and their derivatives' - erika


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
Notox toxicity analysis of molecules and their derivatives l.jpg

NoTox: Toxicity Analysis of Molecules and their derivatives

Primary Advisor : Professor David J. Wild

Bioinformatics Advisor: Professor Sun Kim.


What is computational toxicology l.jpg
What is Computational Toxicology

  • Computational toxicology is an emerging field that constitutes methodical approaches to analyze the harmful effects on the environment and public health due to exposure to chemicals.

  • Computational toxicology may be defined as the application of the tools developed using computational biology concepts to analyze the risk that some chemicals pose to human health and the environment.


Types of toxicology l.jpg
Types of toxicology

The different types of toxicology include

  • Toxicogenomics

  • Aquatic Toxicology

  • Chemical toxicology

  • Ecotoxicology

  • Environment toxicology

  • Medical Toxicology

  • Forensic Toxicology

    Ref: Wikipedia


How is computational toxicology studies important to biology l.jpg
How is computational toxicology studies important to biology

  • Computational toxicity is an increasingly important field with implications throughout biomedical science and drug discovery. To name a few applications

  • Providing molecular profiling approaches to toxicology

  • Drug toxicity

  • Gene- Drug interaction studies

  • Toxicological analysis of Biological molecules and their derivatives


Shortcomings l.jpg
Shortcomings

  • The shortcomings of most computational toxicology methods are

  • Most toxicity methods concentrate on determining whether a particular compound has toxic properties or not. The methods do not necessarily help in understanding whether modifying a particular molecule synthetically to reduce toxic effects is possible.

  • It also does not concentrate on identifying and analysing the reason for toxicity of most molecules.


Problems analyzed l.jpg
Problems analyzed

  • If we have a toxic molecule, can we find a synthetic alternative that might be non toxic

  • If we have a non-toxic molecule, might it be metabolized or changed in the body to something toxic?

  • We use some cheminformatics representations called SMILES and SMIRKS to deal with these problems


Terminologies smiles smirks l.jpg
Terminologies - SMILES/SMIRKS

  • SMILES is the acronym for Simplified Molecular Input Line Entry Specification.

  • Each molecule has a unique canonicalized SMILES representation (Eg c1ccccc1 represents benzene).

  • SMIRKS is a reaction transform language.

  • In general two different kinds of SMIRKS are in use to show transformations. Functional group transformations and molecular framework modifications. An example for SMIRKS would be

    [O:1]=[C:2][Cl:3].[N:4][H:5]>>[O:1]=[C:2][N:4]

    this is an example of a simple displacement reaction representation


Drug guru literature review l.jpg
Drug Guru - Literature Review

  • Drug Guru is a web based computer software program that applies medicinal chemistry transformation reactions to an input structure.

  • The transformation reactions are medicinal chemistry design rules of thumb taken from other drug discovery programs.

  • The output of this program is a list of analogs that can be used for further synthesis.

    Ref: [1]



Drug guru to notox l.jpg
Drug Guru to NoTox

Drug Guru uses smirks to develop alternative compounds based on medicinal chemistry reactions.

NoTox combines the concept of Drug Guru with a different field – Toxicity.


Notox l.jpg
NoTox

  • Tool to predict alternatives for a given molecule based on reaction transformations

  • Tool to test the toxicity of any given molecule

  • Helps in comparing the toxicity of the original and the derived molecule


Notox input requirements l.jpg
NoTox - Input Requirements

  • The input query (Original molecule) should be in the form of SMILES.

  • The reaction transformations should be in the form of SMIRKS

  • The SMIRKS used are a more specific form of the reaction.



Smirksgen l.jpg
Smirksgen

  • The program generates derivatives for a given molecule based on the specified reaction transformation rules.

  • Openeye software for library generation

  • The smirksgen program is developed in Python and it takes in input from a GUI developed using HTML


Toxicity prediction using toxtree l.jpg
Toxicity prediction using Toxtree

  • Toxtree is an open source application that uses the decision tree approach to identify the toxicity of a molecule represented as SMILES.

  • It provides 5 plugins. In NoTox, we make use of the Cramer's rule decision tree approach to determine toxicity.

  • The input molecules are classified in the increasing levels of toxicity as Class 1, Class II and Class III


Notox features available l.jpg
NoTox - Features available

Apart from Smirksgen and Toxtree,

  • NoTox Provides access to another tool WENDI that helps in the profiling of any particular molecule.

  • NoTox also has a feature that helps in the validation of the input SMILES




Objective l.jpg
OBJECTIVE

  • Identifying a molecule with desirable properties and activity towards the human body.

  • Observing the Toxicological effects due to the activity of the identified molecule .


Why atp l.jpg
WHY ATP??

  • ATP acts as a coenzyme in most intracellular energy transfer reactions.

  • ATP acts as a substrate for kinases in signal transduction pathways.

  • It is a major component of the Krebs cycle.


Mechanism of action of atp and its uses l.jpg
Mechanism of action of ATP and Its Uses

  • The main action of ATP is phosphorylation.

  • A double displacement reaction takes place between the phosphate molecule in ATP and the hydroxyl hydrogen of the reacting molecule.

  • The reaction is depicted as follows.

    R-OH . ATP >> R-O-phosphate . ADP


Testing effect of atp on human body l.jpg
Testing effect of ATP on human body

  • Our objective is to study the toxicological effects of ATP on the human body.

  • We use our tool NoTox to study the toxicological effects due to the reaction of ATP with other molecules.


Input data using smiles l.jpg
Input data Using Smiles

  • The test molecules were obtained by doing a substructure search in pubchem and the test set was a list of 100 molecules that contained a substructure that can react with ATP.

  • The smiles format was obtained for these molecules using the molinspiration software.


The reaction transformations l.jpg
The reaction transformations

  • 500 reactions from Kegg involving ATP were studied and the mechanism of each reaction was observed and generalized to 2 SMIRKS rules one each for aromatic and aliphatic compounds


The result l.jpg
The result

  • The toxicity of the input molecule was usually Class 1 or Class 2

  • The toxicity of the derivative was always found to be Class 3.

  • It was observed that the reaction of a molecule with ATP increases the toxicity of the derivative.

  • This suggests that ATP increases the toxicity in the body when it reacts with the biological molecules.


Evidence for the result l.jpg
Evidence for the result

  • Journal articles substantiate the observed result that ATP increases the toxicity of the molecule it reacts with. Some of the examples of the journal articles are

  • Mallick.N, Rai .LC. Metal induced inhibition of photosynthesis, photosynthetic electron transport chain and ATP content of Anabaena doliolum and Chlorella vulgaris: interaction with exogenous ATP, Biomed Environ Sci. 1992 Sep;5(3):241-50

  • Lundy, Paul ; Frew, R. ; Vair, C. ; Nelson, P. ; Gong, W ,Mediation of Sulfur Mustard Cellular Toxicity by ATP: A Possible Mechanism of Action of Sulfur Mustard Toxicity, ADA412934

  • KOBAYASHI K. ; RATAIN M. J. ; Pharmacodynamics and long-term toxicity of etoposide, Cancer chemotherapy and pharmacology   ISSN 0344-5704   CODEN CCPHDZ


Summary l.jpg
Summary

NoTox can be used to search for non-toxic alternatives to toxic compounds,and to find possible toxic metabolites

  • Initial experiments indicate the method is useful

  • Further work should be carried out to evaluate NoTox for both of theseapplications


Future work l.jpg
Future Work

An evaluation study that looks at the following can be performed

  • Known toxic compounds and their derivatives

  • Use information from metabolic database to evaluate the toxic effects due to any particular metabolic pathway.


References l.jpg
References

  • Kent D.Stewart, Melisa Shiroda, Craig A. James , Drug Guru: A computer Software Program for drug design using medicinal chemistry rules, doi: 10.1016/j. bmc. 2006.06.024

  • Robert J.Kavlock et.al , Computational Toxicology- A state of the Science mini review , doi: 10.1093/toxsci/kfm297

  • Mallick.N, Rai .LC. Metal induced inhibition of photosynthesis, photosynthetic electron transport chain and ATP content of Anabaena doliolum and Chlorella vulgaris: interaction with exogenous ATP, Biomed Environ Sci. 1992 Sep;5(3):241-50

  • Lundy, Paul ; Frew, R. ; Vair, C. ; Nelson, P. ; Gong, W ,Mediation of Sulfur Mustard Cellular Toxicity by ATP: A Possible Mechanism of Action of Sulfur Mustard Toxicity, ADA412934

  • KOBAYASHI K. ; RATAIN M. J. ; Pharmacodynamics and long-term toxicity of etoposide, Cancer chemotherapy and pharmacology   ISSN 0344-5704   CODEN CCPHDZ 

  • www.daylight.com

  • www.eyesopen.com

  • http://ambit.acad.bg/toxTree/

  • Wikipedia


Acknowledgements l.jpg
Acknowledgements

  • Professor David Wild

  • Professor Sun Kim

  • The faculty of the Bioinformatics and the Cheminformatics department.

  • Linda Hostetter and Rachel Lawmaster.



ad