4. Our Premise:
computational modeling of cancer processes
and treatments can help find new
chemotherapy compounds and guide clinical
delivery of treatments to improve cure rates
5. Key Objectives:
Develop large-scale computational modeling of
cancer processes and treatments
Find effective chemotherapy compounds (new and
repurposed) and modalities of their clinical delivery to
improve cure rates
Experiment with novel techniques of attacking
cancer cells
6. Microtubules 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.
11. Tubulin Structure
basic unit is dimer, two
protein chains
each chain is linked
amino acids
chain has compact,
folded form
backbone shows chain
structure
13. Different Sequences—
Different Properties
sequences differ in
shape
• chemistry
• movement
tubulins differ
• human isotypes
• between species
14. Spatial Fitting of Drugs
Utilizes the visual
inspection of a Target
binding site within a
target, followed by
the modification of a
drug to produce
better binding to the
target.
19. Known tubulin inhibitors are not
isotype specific
-hence side effects…but:
“Conceivably, if one knew the tubulin isotype and
microtubule regulatory protein composition of a
specific tumor cell, one could design or choose drugs to
selectively target that tumor”
Jordan and Wilson, Nature Reviews Cancer, 2004
20. Tubulin Amino Acids Involved in
Colchicine Binding
class I EPYNATLSVH QLVENTDETYCIDNEALYDICFRTLKLTTPTY G DLNHLVSATM S G VTTCL 240
class II EPYNATLSVH HLVENTDETYSIDNEALYDICFRTLKLTTPTY G DLNHLVSATM S G VTTCL 240
class II
I EPYNATLSIHQLVENTDETYCIDNEALYDICFRTLKLATPTY G DLNHLVSATM S G VTTSL 240
class VI EPYNAVLSIHQLIENAD A CFCIDNEALYDICFRTLKLTTPTY G DLN HLVSLTM S GITTSL 240
* * * * : : : * * :* * * * * * * * * * * * * * * * : * *
* *.****: .* * * * * * *.* * * * * * :**.
class I RFPG Q LNA DLRKLAV N M VPFPRLHFF MP GFAPLTSRG S Q Q Y R ALTVPELTQ Q VFDA K N M M 300
class II RFPG Q LNA DLRKLAV N M VPFPRLHFF MP GFAPLTSRG S Q Q Y R ALTVPELTQ Q M F D SK N M M 300
class II
I RFPG Q LNA DLRKLAVN M VPFPRLHFF MP GFAPLTARG S Q Q Y R ALTVPELTQ Q MF D A K N M M 300
class VI RFPGQL N A DLR KLAVNM V PFPRLHFF MPGF APLTA Q G S Q Q YR ALSVAELT Q Q M F D A R N T M 300
* * * * * * * * * * * * * * . * * : * * *.:. * * : *: *
* * * * * * * * * * * * * ** * * : * * ** ** * * * : *
class I AACDPR H G RYLTVA AVFRG R M S M K EVDE Q M LNV Q N K NSSYFVEWIPN NV K TAVC DIPPR G 360
class II AACDPR H G RYLTVA AIFRG R M S M K EVDE Q M LNV Q N K NSSYFVEWIPN NV K TAVC DIPPR G 360
class II
I AACDPR H G RYLTVATVFRG R M S M K EVDE Q M LAIQSK N SSYFVEWIPN NV K VAVC DIPPR G 360
class VI AACDLRR G RYLTVACIFR G K M STKEVD Q Q LLSV QTRNSSCFVEWIPNNVKVAVC DIPPR G 360
* * * * * * *: * * : * : : : : * *: : * * . * * * *
* : * . * * . * * * : * * * .* * * * * * * *
21. The Colchicine Binding Site:
βII and βIII Tubulin
βII βIII
Thr 353
Cys 239 Val 353 Ser 239
Tyr 200
Arg 200
25. Quantum Mechanical Method
A method that is applicable for calculating atomic and molecular
properties of any system without the need for parameterization
An approach that describes the dynamic distribution of electrons in
the system
Can calculate molecular geometries, transition states, spectra, etc.
A powerful method for predicting stability of molecules and
energetics of chemical reactions
27. Comparison of Molecular Mechanics and Quantum
Mechanical Approach for Molecular Dynamics
Classical MD Quantum Mechanical MD
• Simplified description of the atomic • Atomic / molecular interactions are
configurations and interactions in calculated directly from first principles
the system
• Forces acting on the system are defined • Forces acting on the system are directly
using fixed sets of parameters (i.e. force calculated
fields)
• Computationally fast: • Computationally expensive:
thousand-million atoms < 500 atoms
• Dynamic distribution of electrons in the • Dynamic distribution of electrons in the
system is NOT described system is described
• Difficult to model chemical bond • Easily handles bond making / bond
making / bond breaking processes breaking
28. Hybrid QM/MM MD simulation
QM
MM
Coupling of QM and MM modeling
QM - an active site;
a reaction center; Tubulin-colchicine
solute
MM - enzyme structure;
explicit solvent
29. Our strategy:
Exquisite design of drugs for patient-specific
protein expression using clues from Mother
Nature
Chemical Synthesis
In Vitro and In Vivo Testing
Further Improvement and Refinement
30. Our other projects:
Ultrasound resonance
Electroporation
Magnetic field guided drug delivery
Laser-induced activation of conjugated
compounds
Microtubule hybridization
Taxane pharmacokinetics