Computational Toxicology and Virtual Computational Toxicology and Virtual Development in Drug DesignDevelopment in Drug Design

Dale E. Johnson, Pharm.D., Ph.D. Dale E. Johnson, Pharm.D., Ph.D. Chief Scientific OfficerChief Scientific Officer

ddplatform LLCddplatform LLC

The “Solution” for R&D The “Solution” for R&D

• ~ $700 MM and over 10 years to develop ~ $700 MM and over 10 years to develop novel drug novel drug

• Approximately 75% of overall R&D cost Approximately 75% of overall R&D cost attributed to failures attributed to failures

The “Problem” in pharmaceutical R&DThe “Problem” in pharmaceutical R&D

• Identify/eliminate problematic drugs earlyIdentify/eliminate problematic drugs early

• Design desirable properties into drugs Design desirable properties into drugs

Drug Discovery: the hunting processDrug Discovery: the hunting process where is toxicology today?where is toxicology today?

Target Target SelectionSelection

Lead Lead IdentificationIdentification

Lead Lead OptimizationOptimization

• Identification of Identification of potential potential targetstargets

• Screen developmentScreen development • Lead explosion/ Lead explosion/ optimizationoptimization

• Target verificationTarget verification • High-throughput High-throughput screeningscreening

• Potency in diseasePotency in disease

• Target selectionTarget selection • Secondary assays/ Secondary assays/ mechanism of actionmechanism of action

• PharmacokineticsPharmacokinetics

• Hits to leadsHits to leads • Early toxicologyEarly toxicology

From: Rosamond and Allsop, Science 287, 1973 (2000)

Early toxicology at the Lead Optimization Step: still a Early toxicology at the Lead Optimization Step: still a high failure rate – high cost to R&D high failure rate – high cost to R&D

Chemical LibrariesChemical Libraries

Primary & secondary

efficacy screening

Secondary in vitro

screening

In vivo andmechanistic

screens

Lead selection

ADME, PK, TOX Lead optimization

DevelopmentCandidate

Phase I, II

IND enabling studies

65%Drop Out

The toxicology solutionThe toxicology solution

• Incorporate predictive toxicology concept Incorporate predictive toxicology concept throughout discovery & developmentthroughout discovery & development

• Design reduced toxicity into chemical Design reduced toxicity into chemical libraries libraries

• Create expert systems to accelerate and Create expert systems to accelerate and increase success rate increase success rate – Expert systems must be multi-disciplinary for Expert systems must be multi-disciplinary for

real impactreal impact

Major needs in Predictive Toxicology:Major needs in Predictive Toxicology: Recent industry surveys Recent industry surveys

• Predictive software with updated Predictive software with updated databasesdatabases

• Improved data mining capabilitiesImproved data mining capabilities

• Enhanced in vitro mechanistic screensEnhanced in vitro mechanistic screens

• Ready access to human hepatocytes and Ready access to human hepatocytes and other cellsother cells

• Relevant application of new technologies Relevant application of new technologies ie. toxicogenomicsie. toxicogenomics

Major needs in Predictive Toxicology:Major needs in Predictive Toxicology: Recent industry surveys Recent industry surveys

• Predictive software with updated Predictive software with updated databasesdatabases

• Improved data mining capabilitiesImproved data mining capabilities

• Enhanced in vitro mechanistic screensEnhanced in vitro mechanistic screens

• Ready access to human hepatocytes and Ready access to human hepatocytes and other cellsother cells

• Relevant application of new technologies Relevant application of new technologies ie. toxicogenomicsie. toxicogenomics

Missing elements in the toolboxMissing elements in the toolbox

• Quality dataQuality data from controlled sources from controlled sources

• Newly created database(s)Newly created database(s) using using “pharmaceutical” chemical space“pharmaceutical” chemical space

• Multi-disciplinary chem-toxMulti-disciplinary chem-tox Information / Information / decision toolsdecision tools– Data mining via “med chem building blocks”Data mining via “med chem building blocks”

• FlexibilityFlexibility to incorporate all data from to incorporate all data from internal and external sourcesinternal and external sources

• Web-basedWeb-based, platform independent, platform independent

LeadScopeLeadScopeTMTM Technology Technology

• Structural analysis based on familiar Structural analysis based on familiar structural featuresstructural features

• Powerful graphical representations and Powerful graphical representations and dynamic queryingdynamic querying

• Refine structure alerts to reflect new assay Refine structure alerts to reflect new assay resultsresults

• Statistically test structural hypothesesStatistically test structural hypotheses

RTECS database & liver toxicity RTECS database & liver toxicity

• ~7000 compounds with liver toxicity codes~7000 compounds with liver toxicity codes

• Expert conversion to grades (risk) Expert conversion to grades (risk) – Ordinal ranks using severity of findings, dose, Ordinal ranks using severity of findings, dose,

regimen, species regimen, species

• Create 1Create 1oo liver tox – chemical space liver tox – chemical space

• Data mining with ToxScopeData mining with ToxScopeTMTM: correlations : correlations between chemical structure and liver between chemical structure and liver toxicitytoxicity

Information Windows

Feature Hierarchy Graphic Panel Filter Panel

Portion of the Heterocycles hierarchy showing 3 levels of the pyridine subhierarchy

Portion of the Heterocycles hierarchy showing 3 levels of the pyridine subhierarchy

Selected subset of compounds containing a pyridine substructure with an acyclic alkenyl group in the 2-position

Subset contains 2 compounds

Selected subset of compounds containing a pyridine substructure with an acyclic alkenyl group in the 2-position

Subset contains 2 compounds

Each structure feature in the hierarchy is defined as a substructure search query

Structural definition

atom and bond restrictions

Each structure feature in the hierarchy is defined as a substructure search query

Structural definition

atom and bond restrictions

Compounds containing a pyridine, 2-(alkenyl, acyc) substructure

Compounds containing a pyridine, 2-(alkenyl, acyc) substructure

Uncovering bias in chemical space Uncovering bias in chemical space within data setswithin data sets

• Detect + and – coverage within a desired Detect + and – coverage within a desired chemical spacechemical space

• Understand decision errors that can be Understand decision errors that can be introduced with biased spaceintroduced with biased space

Structural alertsStructural alerts

• Can rapidly find structural alerts

• Can view new libraries in relation to structural alerts

• Can evaluate impact of alert on optimization scheme

RTECS grade 5 only

ToxScopeToxScopeTM TM ComponentsComponents

• LeadScopeLeadScopeTM TM Enterprise TechnologyEnterprise Technology

• Several public or commercial databasesSeveral public or commercial databases

• New databases using “pharmaceutical" New databases using “pharmaceutical" chemical spacechemical space

– New specific organ toxicity databaseNew specific organ toxicity database* Structural alerts Structural alerts

– Continual updates on target organsContinual updates on target organs

ConclusionConclusion

“… “… an an in silicoin silico revolution is revolution is emerging that will alter the conduct emerging that will alter the conduct of early drug development in the of early drug development in the future.”future.”

““Preclinical safety must transition Preclinical safety must transition from an experimental-based process from an experimental-based process into a knowledge-based, predictive into a knowledge-based, predictive process, where experimentation is process, where experimentation is used primarily to confirm existing used primarily to confirm existing knowledge”knowledge”

Acknowledgements Acknowledgements Grushenka Wolfgang, Co-authorGrushenka Wolfgang, Co-author

Julie RobertsJulie Roberts Kevin CrossKevin CrossBill SnyderBill Snyder Michael CrumpMichael CrumpChris FreemanChris Freeman Jeff MillerJeff MillerDon SwartzDon Swartz Michael MurrayMichael MurrayIlya UtkinIlya Utkin Mark BalbesMark BalbesWayne JohnsonWayne Johnson Zhicheng LiZhicheng LiAllen RichonAllen Richon Yan WangYan WangPaul BlowerPaul Blower Limin YuLimin YuGlenn MyattGlenn Myatt Sighle BrackmanSighle BrackmanEmily JohnsonEmily Johnson Lisa BalbesLisa Balbes