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Thursday, October 16, 2014
“Sweet Science: Having Fun with Candy
Chemistry”
Dr. Rich Hartel, University of Wisconsin-Madison
Dr. Matt Hartings, American University
Thursday, October 23, 2014
“Planet of Viruses”
Dr. Carl Zimmer, Author and New York Times Columnist
Beth Hamelin, Chemist, Centers for Disease Control & Prevention
10/9/2014
7
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Co-produced with the American Crystallographic Association
www.amercrystalassn.org
Photo Credit: ACA
A) William Lipscomb and Herbert Hauptman at
an IUCr Congress and General Assembly.
B) Irving Langmuir, J.D. Bernal and Dorothy
Hodgkin at the 1937 British Association
Meeting.
C) Walter Hamilton, Helen Berman, and Tom
Koetzle on their way to a meeting in Aarhus in
1972.
D) Richard E. Marsh and Linus Pauling, at
Caltech during Pauling's 85th birthday
celebration in 1986.
ACA History through photos! A B
C D
14
“From Molecules to Medicine: How Structure Helps Cure Disease”
Recordings will be available to ACS members after three weeks
www.acs.org/acswebinars
Dr. Martha Teeter President,
American Crystallographic
Association
Dr. Greg Petsko Professor of Neurology,
Weill Cornell Medical College
This ACS Webinar is co-produced with the American Crystallographic Association
10/9/2014
8
From Molecules To Medicines:
How Structure Helps Cure Disease
APP
Amyloidogenic
Non-
Amyloidogenic
Gregory A. Petsko
Appel Alzheimer’s Disease Research Institute
Weill Cornell Medical College, New York, NY 10021 USA
Structural Biology In The Age Of
Genomics
EVERY APPROVED DRUG REQUIRES
- Synthesis of 6,200 chemical compounds
- 21 compounds tested in subacute
toxicology
- 7 compounds tested in humans
- 3 compounds in Phase III clinical trials
- 13 years and $450 million
In 2013 in the U.S., on average…
$850 million
10/9/2014
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Where do most drugs candidates fail?
Audience Survey Question
17
• Phase I (toxicity)
• Phase II (efficacy)
• Phase III (head-to-head against best available
therapy)
• Junior High
The Answer
Most drugs (~60%) fail
in Phase II (efficacy)!
10/9/2014
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Why do most drugs fail in Phase II?
Audience Survey Question
19
• They don’t hit the intended target
• They have poor bioavailability
• The target is not a valid target for the human
disease
• They didn’t study for the test
The Answer
The target is not a valid target for the human
disease. What this means:
Our animal models for toxicity and
pharmacokinetics are pretty good.
Our animal models for disease are not.
10/9/2014
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Incidence is >300,000 cases/yr in the USA –
One every 4 seconds worldwide
Prevalence is 5,500,000 in USA
Mean survival after diagnosis is ~10 years
10% of cases are genetic; rest are sporadic
and idiopathic
Current drug market is ~$10 billion
First gene discovered was APP; now more
than 5 others. Most important are APP and
presenilin (γ-secretase). Most important
risk factors are ApoE2 (protective) and
ApoE4 (increased risk). APP A563T
mutation is also protective
Alzheimer’s Disease
What is the fastest-growing demographic group in the United States?
Audience Survey Question
22
• Children
• Young adults
• Octogenarians and older
• Unemployed PhDs
10/9/2014
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National Vital Statistics Report, Feb. 2001
The Answer: Octogenarians and Above
The Problem With Living Longer
Alzheimer’s Disease Parkinson’s Disease ALS
10/9/2014
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Alois Alzheimer Auguste Deter
Plaques and Tangles in the Brain
of Auguste Deter
10/9/2014
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Neurodegenerative diseases are characterized
by dense aggregates of misfolded proteins
AD β-amyloid PD or LBD α-synuclein ALS SOD1
AD or FTD tau ALS or FTD TDP-43 ALS or FTD FUS
What is the toxic species?
tau
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Most significant change in vulnerable brain
regions in early AD
VPS35 (Vacuolar Protein Sorting gene 35)
Originally discovered in yeast
Involved in protein trafficking
Conserved in all eukaryotes
Component of the retromer
multiprotein complex
All components are down by 2-3x in
Vulnerable brain regions in early AD
Retromer
Images Courtesy of Shutterstock
BACE1
10/9/2014
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Retromer
Images Courtesy of Shutterstock
Too little
retromer
Retromer
Images Courtesy of Shutterstock
Retromer
overexpression
10/9/2014
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Stabilization of Unstable Mutant Forms of Glucocerebrosidase
as a Therapeutic Approach for Gaucher Disease
Lieberman et al., Nat. Chem. Biol. (2007)
The MSCS Method Can Map the Binding
Surface of any Crystalline Protein
10/9/2014
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Finding Protein Ligands by in Silico Screening
Screen top ~200
predicted ligands
based on calculated
interaction energy
Library of
>14 million
compound
structures
3D structure
of target
With thanks to Tack Kuntz and Brian Shoichet
In silico screening (docking) can increase the hit rate of a subsequent real screen by:
Audience Survey Question
36
• 10-50x
• 100-300x
• 1,000–5,000x
• 0; it doesn’t help at all
10/9/2014
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The Answer
In silico screening (docking) can increase
the hit rate of a subsequent real screen by
1,000–5,000x
Typically, it s only necessary to screen the
top 100-200 predicted binders for real in
order to get 5-10 compounds that actually
bind
VPS29/35 Interface: The Weak Link
-VPS35 protein levels are
decreased in Alzheimer’s
-Weakest link in Retromer
structure is interface with 29
A. Hierro et al. 2007
10/9/2014
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VPS35/VPS29 Complex
The Retromer Core Complex (VPS35,
VPS26 and VPS29) unfolds at ~49oC
10/9/2014
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0
0.2
0.4
0.6
0.8
1
1.2
0 10 20 30 40 50 60 70 80 90 100
Fra
cti
on
Pro
tein
Un
fold
ed
Temperature (Celcius)
Inactive Compound Titration
2 mM
1 mM
0.5 mM
0.25 mM
0.125 mM
62.5 uM
31.25 uM
15.625 uM
No Compound
Retromer with Best Compound (R55):
a 10oC Stabilization
10/9/2014
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R55
Dramatic R55-dependent Reduction in
the Amount of APP in Late Endosomes
Human Molecular Genetics, 2012
10/9/2014
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R55 Lowers Aβ Levels in Cortical Neurons
from an Alzheimer’s Patient
R55 Lowers Level of Aβ in a Dose-
dependent Manner
10/9/2014
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R55 Increase in Retromer Level is
Inversely Correlated with Level of Aβ
βCTF
Fragment Pattern is Exactly as Predicted
R55
10/9/2014
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Retromer Link to
Familial Parkinson’s Disease
The American Journal of Human Genetics 89, 162–167, July 15, 2011
The American Journal of Human Genetics 89, 168–175, July 15, 2011
VPS35 Expression is Reduced in the Substantia
Nigra and Cerebral Cortex of PD Patients
10/9/2014
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• We have previously reported that
overexpression of VPS35 rescues defects
observed in LRRK2 G2019S models both in
vitro and in cultured rodent neurons (shortened
neurites, trafficking defects, and lysosomal
abnormalities).
• MacLeod, D.A., Rhinn, H., Kuwahara, T., Zolin, A., Di Paolo, G.,
McCabe, B.D., Marder, K.S., Honig, L.S., Clark, L.N., Small, S.A., et
al. (2013). RAB7L1 interacts with LRRK2 to modify intraneuronal
protein sorting and Parkinson's disease risk. Neuron 77, 425-439.
• Do the retromer pharmacological chaperones
do the same?
R55 Rescues Primary Neurons in Rat
Models of VPS35 and LRRK2-dependent PD
10/9/2014
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Dagmar Ringe Vincent Mecozzi Shulin Ju
Scott Small Asa Abeliovich Diego Berman
Further Reading Mecozzi VJ, Berman DE, Simoes S, Vetanovetz C, Awal MR, Patel VM, Schneider RT, Petsko GA,
Ringe D, Small SA. “Pharmacological chaperones stabilize retromer to limit APP processing.”
Nature Chem Biol. Apr 20. 10:443-449 (2014).
Petsko, GA. “The Coming Epidemic of Neurologic Disorders: What Science Is – and Should Be –
Doing About It.” Daedalus, Summer 2012, Vol. 141, No. 3, Pages 98-107
Ringe D, Petsko GA. “What are pharmacological chaperones and why are they interesting?”
J Biol. (now BMC Biology) 8(9):80-83 (2009).
Landon MR, Lieberman RL, Hoang QQ, Ju S, Caaveiro JM, Orwig SD, Kozakov D, Brenke R, Chuang
GY, Beglov D, Vajda S, Petsko GA, Ringe D. “Detection of ligand binding hot spots on protein
surfaces via fragment-based methods: application to DJ-1 and glucocerebrosidase.” J Comput
Aided Mol Des. 23[8]:491-500 (2009).
Lieberman RL, D'aquino JA, Ringe D, Petsko GA. “Effects of pH and iminosugar pharmacological
chaperones on lysosomal glycosidase structure and stability.” Biochemistry. 48(22):4816-4827
(2009).
Lieberman RL, Wustman BA, Huertas P, Powe AC Jr, Pine CW, Khanna R, Schlossmacher MG, Ringe
D, Petsko GA. “Structure of acid beta-glucosidase with pharmacological chaperone provides
insight into Gaucher disease.” Nature Chem Biol. 3(2):101-107 (2007).
Ringe, D. and Petsko, G.A. "The Age of Structure: The Role of Protein Crystallography in Drug
Design", New Perspectives in Drug Design, Academic Press Ltd. (1995).
10/9/2014
28
55
“From Molecules to Medicine: How Structure Helps Cure Disease”
Recordings will be available to ACS members after three weeks
www.acs.org/acswebinars
Dr. Martha Teeter President,
American Crystallographic
Association
Dr. Greg Petsko Professor of Neurology,
Weill Cornell Medical College
This ACS Webinar is co-produced with the American Crystallographic Association
56
Co-produced with the American Crystallographic Association
www.amercrystalassn.org
Photo Credit: ACA
A) William Lipscomb and Herbert Hauptman at
an IUCr Congress and General Assembly.
B) Irving Langmuir, J.D. Bernal and Dorothy
Hodgkin at the 1937 British Association
Meeting.
C) Walter Hamilton, Helen Berman, and Tom
Koetzle on their way to a meeting in Aarhus in
1972.
D) Richard E. Marsh and Linus Pauling, at
Caltech during Pauling's 85th birthday
celebration in 1986.
ACA History through photos! A B
C D
10/9/2014
29
Upcoming ACS Webinars www.acs.org/acswebinars
57
®
Contact ACS Webinars ® at [email protected]
Thursday, October 16, 2014
“Sweet Science: Having Fun with Candy
Chemistry”
Dr. Rich Hartel, University of Wisconsin-Madison
Dr. Matt Hartings, American University
Thursday, October 23, 2014
“Planet of Viruses”
Dr. Carl Zimmer, Author and New York Times Columnist
Beth Hamelin, Chemist, Centers for Disease Control & Prevention
58
“From Molecules to Medicine: How Structure Helps Cure Disease”
Recordings will be available to ACS members after three weeks
www.acs.org/acswebinars
Dr. Martha Teeter President,
American Crystallographic
Association
Dr. Greg Petsko Professor of Neurology,
Weill Cornell Medical College
This ACS Webinar is co-produced with the American Crystallographic Association
10/9/2014
30
Be a featured fan on an upcoming webinar! Write to us @ [email protected]
59
How has ACS Webinars benefited you?
®
“As a tenure-track faculty member, I do not have
time to keep up with the advances in every
division of chemistry. By viewing ACS Webinars,
I can keep up with recent advances.”
Sherri Young,
Assistant Professor of Chemistry,
Muhlenberg College
60
facebook.com/acswebinars
@acswebinars
youtube.com/acswebinars
10/9/2014
31
Benefits of ACS Membership
61 www.acs.org/2joinACS
Chemical & Engineering News (C&EN) The preeminent weekly news source.
NEW! Free Access to ACS Presentations on Demand® ACS Member only access to over 1,000 presentation recordings from recent ACS meetings and select events.
NEW! ACS Career Navigator Your source for leadership development, professional education, career services, and much more.
ACS Webinars does not endorse any products or
services. The views expressed in this presentation
are those of the presenter and do not necessarily
reflect the views or policies of the American
Chemical Society.
62
®
Contact ACS Webinars ® at [email protected]
10/9/2014
32
Upcoming ACS Webinars www.acs.org/acswebinars
63
®
Contact ACS Webinars ® at [email protected]
Thursday, October 16, 2014
“Sweet Science: Having Fun with Candy
Chemistry”
Dr. Rich Hartel, University of Wisconsin-Madison
Dr. Matt Hartings, American University
Thursday, October 23, 2014
“Planet of Viruses”
Dr. Carl Zimmer, Author and New York Times Columnist
Beth Hamelin, Chemist, Centers for Disease Control & Prevention
