Jack TuszynskiJack Tuszynski

Cross Cancer InstituteCross Cancer InstituteEdmonton, AlbertaEdmonton, Alberta

Mathematical Mathematical ModellingModelling and Pharmaceutical and Pharmaceutical DevelopmentDevelopment

*Rebuilding a Research Team**Rebuilding a Research Team*

TorinTorin HuzilHuzil, PhD , PhD VahidVahid RezaniaRezania, PhD, PhD

AvnerAvner PrielPriel, PhD, PhD--IsraelIsraelPrzemekPrzemek ChelminiakChelminiak, PhD, PhD--UKUK

Linda Linda PayetPayet, PhD, PhDRebeccahRebeccah Marsh, Marsh, M.ScM.Sc..--USUS

Eric Carpenter, B.Sc. Eric Carpenter, B.Sc. Melissa Melissa GajewskiGajewski, , BScBSc

Evan Kelly, Evan Kelly, BScBScTravis Craddock, Travis Craddock, BScBSc

Tyler Tyler LuchkoLuchko, B.Sc. Hon. , B.Sc. Hon. Kristy Kristy BeinertBeinert, student, studentJoseph Joseph HajdukHajduk, student, student

Standard Cancer Treatment Modalities:Standard Cancer Treatment Modalities:

Radiation therapyRadiation therapyChemotherapyChemotherapySurgerySurgeryGene TherapyGene Therapy

Our Premise:Our Premise:computational modeling of cancer processes computational modeling of cancer processes and treatments can help find new and treatments can help find new chemotherapy compounds and guide clinical chemotherapy compounds and guide clinical delivery of treatments to improve cure ratesdelivery of treatments to improve cure rates

Key Objectives:Key Objectives:

Develop largeDevelop large--scale computational modeling of scale computational modeling of cancer processes and treatmentscancer processes and treatments

Find effective chemotherapy compounds (new and Find effective chemotherapy compounds (new and repurposed) and modalities of their clinical delivery to repurposed) and modalities of their clinical delivery to improve cure ratesimprove cure rates

Experiment with novel techniques of attacking Experiment with novel techniques of attacking cancer cellscancer cells

Microtubules and CancerMicrotubules and Cancer

One of the critical components of cell division are the microtubules. We selectively target microtubules,

disrupting cell division, thereby killing dividing cells.

The presence of several human tubulin isoforms provides us with a unique platform on which to develop drugs that have increased specificities for those expressed in cancerous cells.

Understanding MicrotubulesUnderstanding Microtubules

MicrotubulesMicrotubules

Zeroing in on the targetZeroing in on the target

Simulating MicrotubulesSimulating Microtubules

TubulinTubulin StructureStructure

basic unit is dimer, two basic unit is dimer, two protein chainsprotein chainseach chain is linked each chain is linked amino acidsamino acidschain has compact, chain has compact, folded formfolded formbackbone shows chain backbone shows chain structurestructure

Protein Backbone StructureProtein Backbone Structure

Two common formsTwo common forms

•• αα--helixhelixhelical backbonehelical backbone

•• ββ--sheetsheetstraight, parallel straight, parallel backbone sectionsbackbone sections

Different SequencesDifferent Sequences——Different PropertiesDifferent Properties

sequences differ insequences differ inshapeshape

•• chemistrychemistry•• movementmovement

tubulinstubulins differdiffer•• humhuman an isotypesisotypes•• between speciesbetween species

Spatial Fitting of DrugsSpatial Fitting of Drugs

Utilizes the visual inspection of a binding site within a target, followed by the modification of a drug to produce better binding to the target.

Target

Binding pockets for Binding pockets for colchicinecolchicine and and taxanestaxanes

docetaxel

paclitaxel

colchicine

Paclitaxel from the Pacific Yew

Colchicine from Autumn Crocus

Vinca alkaloids from periwinkle

Known Known tubulintubulin inhibitors are not inhibitors are not isotypeisotype specificspecific

--hence side effectshence side effects……but:but:““Conceivably, if one knew the Conceivably, if one knew the tubulintubulin isotypeisotype and and

microtubule regulatory protein composition of a microtubule regulatory protein composition of a specific tumor cell, one could design or choose drugs to specific tumor cell, one could design or choose drugs to selectively target that tumorselectively target that tumor””

Jordan and Wilson, Nature Reviews Cancer, 2004Jordan and Wilson, Nature Reviews Cancer, 2004

Tubulin Amino Acids Tubulin Amino Acids IInvolved in nvolved in Colchicine Colchicine BBindinginding

class I EPYNATLSVHQLVENTDETYCIDNEALYDICFRTLKLTTPTYGDLNHLVSATMSGVTTCL 240class II EPYNATLSVHHLVENTDETYSIDNEALYDICFRTLKLTTPTYGDLNHLVSATMSGVTTCL 240class III EPYNATLSIHQLVENTDETYCIDNEALYDICFRTLKLATPTYGDLNHLVSATMSGVTTSL 240class VI EPYNAVLSIHQLIENADACFCIDNEALYDICFRTLKLTTPTYGDLNHLVSLTMSGITTSL 240

*****.**:*:*:**:* :.********** *****.************ *:**:**.*

class I RFPGQLNADLRKLAVNMVPFPRLHFFMPGFAPLTSRGSQQYRALTVPELTQQVFDAKNM M 300class II RFPGQLNADLRKLAVNMVPFPRLHFFMPGFAPLTSRGSQQYRALTVPELTQQ MFDSKNM M 300class III RFPGQLNADLRKLAVNMVPFPRLHFFMPGFAPLTARGSQQYRALTVPELTQQ MFDAKNM M 300class VI RFPGQLNADLRKLAVNMVPFPRLHFFMPGFAPLTAQGSQQYRALSVAELTQQMFDARNTM 300

****************************.*****::******.*:*.*****:**::* *

class I AACDPRHGRYLTVAAVFRGR MSMKEVDEQ M LNVQNKNSSYFVEWIPNNVKTAVCDIPPRG 360class II AACDPRHGRYLTVAAIFRGR MSMKEVDEQ M LNVQNKNSSYFVEWIPNNVKTAVCDIPPRG 360class III AACDPRHGRYLTVATVFRGR MSMKEVDEQ M LAIQSKNSSYFVEWIPNNVKVAVCDIPPRG 360class VI AACDLRRGRYLTVACIFRGK MSTKEVDQQLLSVQTRNSSCFVEWIPNNVKVAVCDIPPRG 360

** * *:* ***.* :*** *. :***:*:: :* :*** *.:*:*****.******* *

The The CColchicine olchicine BBinding inding SSite: ite: ββII and II and ββIII TubulinIII Tubulin

Thr 353Cys 239

Tyr 200

Val 353 Ser 239

Arg 200

βII βIII

Colchicine Bound to Colchicine Bound to ββII and II and ββIII TubulinIII Tubulin

βII βIII

Colchicine Colchicine DDerivatives that may erivatives that may DDifferentiate ifferentiate IIsoformssoforms

6 memberedaromatic ring

5 memberedring

extendedmethyl

extendedhydroxyl

Colchicine Colchicine DDerivatives erivatives BBound ound to Tubulin to Tubulin IsoformsIsoforms

Void

βII βIII

Quantum Mechanical MethodQuantum Mechanical Method

A method that is A method that is applicable for calculatapplicable for calculating atomic and molecular ing atomic and molecular properties of properties of any any system without the need for parameterizationsystem without the need for parameterization

An approach that describes the dynamic distribution of electronsAn approach that describes the dynamic distribution of electrons in in the systemthe system

Can cCan calculate molecular geometries, transition states, spectra, etc.alculate molecular geometries, transition states, spectra, etc.

A powerful method for predicting stability of molecules and A powerful method for predicting stability of molecules and energeticsenergetics of chemical reactionsof chemical reactions

Quantum Mechanical OptimizationQuantum Mechanical Optimization(An example)(An example)

Before After

Comparison of Molecular Mechanics and Quantum Comparison of Molecular Mechanics and Quantum Mechanical Approach for Molecular DynamicsMechanical Approach for Molecular Dynamics

Classical Classical MDMD•• Simplified Simplified description of the atomic description of the atomic

configurations and interactions in configurations and interactions in the systemthe system

•• Forces acting on the system are Forces acting on the system are definedefineddusiusing ng fixed sets of parameters (fixed sets of parameters (ii.e. force .e. force fields)fields)

•• Computationally fast: Computationally fast: thousandthousand--million atomsmillion atoms

•• Dynamic distribution of electrons in the Dynamic distribution of electrons in the system is NOT describedsystem is NOT described

•• Difficult to model chemical bond Difficult to model chemical bond making / bond breaking processesmaking / bond breaking processes

Quantum Mechanical MDQuantum Mechanical MD•• Atomic / molecular interactions are Atomic / molecular interactions are

calculated directly from first principlescalculated directly from first principles

•• Forces acting on the system are directly Forces acting on the system are directly calculatedcalculated

•• Computationally expensive:Computationally expensive:< 500 atoms< 500 atoms

•• Dynamic distribution of electrons in the Dynamic distribution of electrons in the system is describedsystem is described

•• Easily handles bond making / bond Easily handles bond making / bond breakingbreaking

Hybrid QM/MM MD simulationHybrid QM/MM MD simulation

Tubulin-colchicine

MMQM

Coupling of QM and MM modelingQM - an active site;

a reaction center; solute

MM - enzyme structure; explicit solvent

Our strategy:Our strategy:

Exquisite design of drugs for patientExquisite design of drugs for patient--specific specific protein expression using clues from Mother protein expression using clues from Mother NatureNatureChemical SynthesisChemical SynthesisIn Vitro and In Vivo TestingIn Vitro and In Vivo TestingFurther Improvement and RefinementFurther Improvement and Refinement

Our other projects:Our other projects:

Ultrasound resonanceUltrasound resonanceElectroporationElectroporationMagnetic field guided drug deliveryMagnetic field guided drug deliveryLaserLaser--induced activation of conjugated induced activation of conjugated compoundscompoundsMicrotubule hybridizationMicrotubule hybridizationTaxaneTaxane pharmacokineticspharmacokinetics