COMPUTER-AIDED PREDICTION COMPUTER-AIDED PREDICTION OF XENOBIOTICS TOXICITY OF XENOBIOTICS TOXICITY

Reporters: Reporters: Zinchenko T.O., Nebesna T.Yu.Zinchenko T.O., Nebesna T.Yu.

Scientific advisers: prof. I. S. Chekman, Scientific advisers: prof. I. S. Chekman,

prof. O.P. Javorovskyprof. O.P. Javorovsky

National O.O. Bogomolets Medical UniversityNational O.O. Bogomolets Medical UniversityDepartment of pharmacology and clinical Department of pharmacology and clinical

pharmacologypharmacology Chief of department: prof. I.S. ChekmanChief of department: prof. I.S. Chekman

Department of hygiene of workDepartment of hygiene of work Chief of department: prof. O.P. JavorovskyChief of department: prof. O.P. Javorovsky

ToxicologyToxicology is the study of the adverse effects of chemicals on living organisms. It is the study of symptoms, mechanisms, treatments and detection of poisoning, especially the poisoning of people.

ToxicityToxicity is the degree to which a substance is able to damage an exposed organism.

A xenobioticA xenobiotic is a chemical which is found in an organism but which is not normally produced or expected to be present in it.

The aim of toxicologyThe aim of toxicology testing is the safety assessment of a substance such as a

new pharmaceutical compound or a pesticide relative to a vehicle or negative control.

Toxicity kindsToxicity kinds:Toxicity kinds: Toxic effect: Specific

toxicity:

Acute Toxicity Reversible toxic effect

Carcinogenicity,Genetic toxicity (mutagenicity),Teratogenicity,Hematotoxicity,Nephrotoxicity,Cardiotoxicity,Immunotoxicity,Hepatotoxicity,Neurotoxicity,Irritation skins

Subchronic Toxicity

Irreversible toxic effect

Chronic Toxicity

Researches QSAR in toxicology of Researches QSAR in toxicology of relation to such biological objects:relation to such biological objects:

QSARQSAR (quantitative structure-(quantitative structure-activity relationshipactivity relationship)

is a mathematical relationship between a biological activity of a molecular system and its geometric and

chemical characteristics.

OSAR applicationOSAR application:

Benefits of Using QSAR Benefits of Using QSAR ModelingModeling

No animal test data are required No need for interspecies uncertainty

factors Increased accuracy, sensitivity and

specificity over animal models (identifies chemical adverse effects not detected in animal studies)

Batch processing(prioritization of large test chemical data sets)

Reduced cost

The aim of QSAR methodThe aim of QSAR method:

analysis of a considerable quantity of descriptors to reject what practically do not influence on under investigation toxicity parameters, and to define what are bound to it.

Biological Activity

Physico-Chemical & Structural Properties

+ (Statistical) Relationship

Prediction Method

(Q)SAR

Evaluation

Toxicology

Pharmacology

Calculated properties

Measuredproperties

ADME

Validation

Computational PredictiveComputational Predictive Toxicology Toxicology

Toxicological Endpoints (e.g., Carcinogenicity, Mutagenicity)

Dose Related Endpoints (e.g., MTD, MRDD, LD50)

Trans-Trans-formedformedToxicityToxicityData Data

ChemicalChemicalStructureStructureDataData

QSARQSARToxicityToxicityResponseResponsePredictions Predictions

ToxicityToxicityDoseDoseData Data

ChemicalChemicalStructureStructureDataData

QSARQSARToxicityToxicityDoseDosePredictionsPredictions

Molecular DescriptorMolecular DescriptorCalculated:Calculated:

Solution to a mathematical procedure that transforms chemical information into a numbersurface areas (polar, non-polar), dipole moment, volume

Experimental:Experimental:the result of some standardized experiment to measure a molecular attribute melting point, partition coeficients, refractive index, etc.

Types of DescriptorsTypes of Descriptors

Types of DescriptorsTypes of Descriptors Counts of features: For example HBAs, HBDs, aromatic

ring systems, substructures/fragments ( e.g. , carbonyl groups, basic nitrogens, carboxyl groups,…),etc.

Physicochemical Properties: LogP, solubility, MW, MP, BP, heat of sublimation, molar refractivity, Hammett parameters, etc.

Topological Indices: Wiener index, branching indices, kappa shape indices, electrotopological state indices, atom-pairs, topological torsions, etc.

BCUTs (3-D, 2-D, 2-T): Electrostatic, charge, and polarizability (hydrophobic).

Others: Volsurf, polar surface area, etc.

3D-QSAR: CoMFA3D-QSAR: CoMFACoComparative mparative MMolecular olecular FField ield

AAnalysisnalysis Select test and training sets of

comparable diversity. Generate 3-D structures (single

conformations). Structurally Align and place in a box

with grid

QSAR modelQSAR model::pLD50=-0.722-(1,30pLD50=-0.722-(1,3010^-4)E10^-4)Eorigorig – (1,63 – (1,6310^-3)E10^-3)Emetmet – –

- (5,00- (5,0010^-5)NASA – (3,6010^-5)NASA – (3,6010^-3)E10^-3)Es203ops203op + (2,91 + (2,9110^-3)E10^-3)Eplspls + +

+ (5,40+ (5,4010^-4)E10^-4)Es203ops203opaged aged – (4,87– (4,8710^-3)E10^-3)Ealgalg + 0,985CoMFA + 0,985CoMFA

RR22=0.90, rmse=0.301, F=45.131.=0.90, rmse=0.301, F=45.131. Eorig Energy of the initial organ phosphorus compound

Emet Energy metabolite

NASA Neural Approach to structure-activity

Es203opEnergy ?

EplsEnergy?

Es203opagdEnergy?

EalgEnergy

CoMFA Comparative Molecular Field Analysis

Programs for toxicity forecastingPrograms for toxicity forecasting:

Programs Designer

DEREK LASHA Limited,http://www.Ihasalimited.org

Oncologic LogiChem Inc.,http://www.logichem.com

HazarExpert CompuDrug,http://www.compudrug.com/hazar

TOPKAT Accelrys Inc.,http://www.accelrys.com/products/topcat

MCASE, CASE,CASETOX MultiCASE Inc.,http://www.multicase.com

Programs for toxicity forecastingPrograms for toxicity forecasting:Programs Designer

ToxScope LeadScope Inc.,http://www.leadscope.cjm/products/txs.htm

ToxFilter Pharma Algorithms Inc.,http://www.Ap-algorithms.com_filter.htm

ECOSAR U.S.Environmental Protection Agency.http://www.epa.gov/oppt/newchems/tools/21ecosar.htm

ToxExpress System Gene Logic,http://www.genelogic.com

ZINC+OpenEye

http://ww.zinc.docking.org; http://www.eyesopen.com/

PASS(Prediction of Activity Spectra PASS(Prediction of Activity Spectra for Substances)for Substances)

Finding most probable new leads with required activity spectra among the compounds from in-house and commercial data bases.

Revealing new effects and mechanisms of action for the old substances in corporate and private data bases.

Providing the basis for selection of the most prospective compounds for high throughput screening from the set of available samples.

Determining the assays that are more relevant for a particular compound.

PASSDEMO.ZIPPASSDEMO.ZIP

Thanks for your attention!