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History and Evolution of CADD:
The Successes, Shortcomings,
and Future Directions
Osman F. Güner, Ph.D.
Copyright © 2009Turquoise Consulting. All Rights Reserved
Primary Goal of Pharmaceutical
Industry
To find, develop, and market “new chemical
entities” (NCEs)...
That can be used against untreatable diseases, or.
That have superior properties compared to
currently available drugs.
What are drugs?
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Drugs Save Lives !
Antibiotics and
vaccines played a
major role in the neareradication of many
major diseases of the
1920s, including
syphilis, diphtheria,
whooping cough,
measles, and polio
Source: U.S. National Center for
Health Statistics, 1999.
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Drugs Save Lives (1965-1996)
Sources: Boston consulting group, “the contribution of
pharmaceuticals companies: what’s at stake for America, September
1993; U.S. National center for health statistics, 1998.
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Drugs Contribute to the Increase of
Life Expectancy
Life expectancy in U.S.:
1920 = 54 years
1960 = 70 years
1999 = 76 years
Every five years since 1965, roughly one
additional year has been added to life
expectancy at birth
Source: PhRMA, 1999
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Drugs Improve the Quality of Life
A pill, an ACE inhibitor that I take daily, keeps my
blood pressure under control
Thanks to anti-nausea drugs (e.g., Zofran),
cancer patients can endure chemotherapy better
Thanks to clot-buster drugs, stroke patients can
escape brain damage
Other reputable life quality improvement drugs:
Rogaine
Prozac
Viagra
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Example: HIV-1 Protease Inhibitors
The death rate from AIDS dropped by nearly half
in 1997—the biggest single-year decline in
history for a major cause of death.
Nearly 16,000 fewer Americans died of AIDS in
1997 than the year before.
AIDS no longer ranks among the top 10 causes
of death in the United States.
Secretary of Health and Human Services Donna E. Shalala
called the news “spectacular.” “It reflects drug
breakthroughs and our ability to get the drugs to people who
are infected,” she said.
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Top Selling HIV-1 Protease
Inhibitor
CRIXIVAN® for AIDS - Merck
Dorsey, B. D. et al. J. Med. Chem.
1994, 37, 3443-3451; Holloway, M. K.
et al. In Computer-Aided Molecular
Design, Reynolds, C. H. et al., Eds.
ACS Symp. Series 589, 1995, 36-50
Indinavir: HIV-1
Protease Inhibitor
developed via X-ray
crystallography,
molecular mechanics
calculations, and
structure-based design
Merck researchers
involved with this study
have received ACS
award for “Creative
Invention”
Chem. Eng. News,
1999, Jan. 11
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Does Only Large Pharmaceutical
Companies Design New Drugs?
HIV Inhibitor Drug Sales
1998 1997 Non-US/US
Rank Rank Brand Name Chemical
52
65
69
70
71
88
104
155
156
228
241
381
410
500
58
45
91
77
402
450
115
214
73
234
326
Crixivan
Epivir
Zerit
BuSpar
Viracept
Combivir
Invirase
Norvir
Retrovir
Videx
Viramune
Sustiva
Hivid
Viracept
Indinavir sulphate
Lamivudine
Stavudine
Buspirone hydrochloride
Nelfinavir mesylate
Lamivudine and zidovudine
Saquinavir mesylate
Ritonavir
Zidovudine
Didanosine
Nevirapine
Efavirenz
Zalcitabine
Nefinavir mesylate
Pharmaceutical
Company
WW sales 1997-1998 Approval
1998 ($M) % Change Date
Merck & Company
Glaxo Wellcome
Bristol-Myers Squibb
Bristol-Myers Squibb
Agouron
Glaxo Wellcome
F. Hoffmann LaRoche
Abbott Laboratories
Glaxo Wellcome
Bristol-Myers Squibb
Boehringer Ingelheim
DuPont
F. Hoffmann LaRoche
F. Hoffmann LaRoche
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675.0
595.0
551.0
531.0
530.1
442.5
397.1
250.0
248.6
162.0
154.0
75.0
65.5
34.5
16.0% 3/13/96
-13.1% 11/17/95
38.4% 6/27/94
19.9% 9/29/96
829.9% 3/14/97
1171.6% 9/26/97
15.0% 12/6/95
47.1%
3/1/96
-47.7% 3/19/87
6.6% 10/9/91
- 6/21/96
9/17/98
0.0% 6/19/92
1/22/98
HIV Inhibitor Via Structure-based
Design
VIRACEPT® for AIDS - Lilly and Agouron
Nelfinavir: HIV-1 Protease
Inhibitor developed via
structure-based design
Kaldor, S.W. et al. J. Med. Chem. 1997, 40, 3979-3985
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Small Biotech Firms With Drugs in
the Market
Agouron
Organized in 1984
An engineering approach to the design of novel synthetic
drugs based upon the molecular structures of target proteins
Released Viracept™ in 1998
Merged with Warner-Lambert (Parke-Davis) in 1999
Vertex
Organized in 1989
Consider themselves a leader in Structure-based drug
design
Agrenerase™ receives FDA approval for treatment of HIV
infection in 1999
Have been receiving many milestone payments from partner
companies and today (as of June 1999), they have about
$204 billion in cash and investments
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Is There Any Room for a New Drug When
There Are Several Treatments Already
Available?
LIPITOR for Cholesterol
reduction - Parke
Davis
“There is still serendipity left
in science… We couldn’t
have predicted that this drug
would have been metabolized
to an active metabolite”
Roger Newton, former ParkeDavis biologist who led the
drug discovery team who
developed Lipitor]
Modern Drug Discovery, March/April1999
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Late Entry, Gaining Market-share
1998 1997 Non-US/US Brand
Rank Rank
Name
Pharmaceutical Company Indicated for...
1
2
3
4
5
6
7
8
6
1
3
7
4
8
34
10
Losec/Prilosec
Zocor
Prozac
Norvasc
Renitec/Vasotec
Clarityne/Claritin
Lipitor
Zoloft
AstraZeneca
Merck & Company
Eli Lilly and Company
Pfizer
Merck & Company
Schering-Plough
Warner-Lambert and Pfizer
Pfizer
9
11
10
32
Seroxat/Paxil
SmithKline Beecham
Premarin, Prempro,
and Premphase
American Home Products
1997 Market
Share
Zocor + Mevacor
= 70%
Lipitor = 0%
WW sales 97-98 % Approval
1998 ($M) Change
Date
Ulcers
Cholesterol reduction
Depression
Hypertension
Hypertension
Allergies
Cholesterol reduction
Depression
Depression and obsessivecompulsive disorder
Menopausal symptoms
and osteoporsis
1999 Market
Share
Zocor + Mevacor
= 40%
Lipitor = 37%
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3976.1
46.9%
3945.0 10.3%
2812.0
10.1%
2575.0
16.1%
2400.0
-4.4%
2300.0
35.3%
2200.0 154.3%
1836.0
21.8%
9/14/89
12/23/91
12/29/87
7/31/92
12/24/85
4/12/93
12/17/96
12/30/91
1757.0
17.9% 12/29/92
1650.0
24.2% 10/16/78
2002+ Market
Share
Lipitor – Most
profitable drug
in the history
Causes of Candidate Failures
in Man 1964-1985
10.1%
10.1%
39.4%
11.1%
29.3%
Pharmacokinetics
Efficacy
Animal Toxicity
Adverse Effects
Business/Other
Source: Prentis, et al., Br. J. Clin. Pharmac. 1988, 25, 387-396
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Cost Maximize for Drugs That Fail
After Hitting the Market
Bromfenac (Duract)
non-steroidal antiinflammatory
from Wyeth-Ayerst
released: May 1997
withdrawn: June, 1998
reason: adverse
hepatotoxic effects
time in market: 11
months
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Again, the Worst Case:
Drugs Failing After the Release
Mibefradil (Posicor)
calcium-channel blocker
from Hoffmann LaRoche
released: May 1997
withdrawn: June 1998
reason: drug-drug
interactions (p450 3A4
inhibition)
time in market: 11
months
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Role of Cytochrome p450 in Drug
Metabolism
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Objectives of CADD
Lead identification:
Discovery of new compounds that have the ability
to exert the biological effect in a desired
therapeutic category
Lead optimization:
Optimization of the lead compound to increase the
desired properties and decrease the undesired
properties
Candidate evaluation:
Evaluate and identify the “winning lead” (or quickly
eliminate the “losing leads”)
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History and Evolution of ComputerAided Drug Design
60s - 70s … QSAR
focus on lead optimization
80s … Molecular Modeling
focus shifting from lead optimization to lead identification
early 90s … 3D Searching, structure-based design (de Novo
design)
focus on lead identification
late 90s … Combinatorial Chemistry, HTS
focus on multiple lead identification
00s … Rational and Combinatorial Drug Design
focus on the leads: “candidate evaluation”
Copyright © 2009 Turquoise Consulting. All Rights Reserved
History and Evolution of ComputerAided Drug Design
60s - 70s … QSAR
focus on lead optimization
80s … Molecular Modeling
focus shifting from lead optimization to lead identification
early 90s … 3D Searching, structure-based design (de Novo
design)
focus on lead identification
late 90s … Combinatorial Chemistry, HTS
focus on multiple lead identification
00s … Rational and Combinatorial Drug Design
focus on the leads: “candidate evaluation”
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Successes with QSAR
NOROXIN®, antibacterial
agent - Kyorin
Pharmaceutical
Norfloxacin: QSAR
techniques were used in
its development.
Following its discovery, 6fluoroquinolones became
a major class of
antibiotics.
Koga, H. et al. J. Med.
Chem. 1980, 23, 13581363.
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Successes with QSAR
COZAAR® for
Hypertension treatment DuPont, Merck
Losartan: Angiotensin II
receptor antagonist
developed via molecular
modeling of a lead
compound from patent
literature and QSAR
Duncia, J. V. et al. J. Med.
Chem. 1990, 33, 1312-1329;
Duncia, J. V. et al. Med. Res.
Rev. 1992, 12, 149-191.
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History and Evolution of ComputerAided Drug Design
60s - 70s … QSAR
focus on lead optimization
80s … Molecular Modeling
focus shifting from lead optimization to lead
identification
early 90s … 3D Searching, structure-based design (de Novo
design)
focus on lead identification
late 90s … Combinatorial Chemistry, HTS
focus on multiple lead identification
00s … Rational and Combinatorial Drug Design
focus on the leads: “candidate evaluation”
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Molecular Visualization
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Successes with Molecular
Modeling
TEVETEN® for
Hypertension - Smithkline
Beecham
Eprosartan: Angiotensin II
receptor antagonist
developed via molecular
modeling of a lead
compound and molecular
overlays
Weinstock, J. et al. J. Med.
Chem. 1991, 34, 1514-1517;
Keenan, R. M. J. Med.
Chem. 1993, 36, 1880-1892.
Copyright © 2009 Turquoise Consulting. All Rights Reserved
History and Evolution of ComputerAided Drug Design
60s - 70s … QSAR
focus on lead optimization
80s … Molecular Modeling
focus shifting from lead optimization to lead identification
early 90s … 3D Searching, structure-based design (de Novo
design)
focus on lead identification
late 90s … Combinatorial Chemistry, HTS
focus on multiple lead identification
00s … Rational and Combinatorial Drug Design
focus on the leads: “candidate evaluation”
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Success with SBD
TRUSOPT® for
Glaucoma treatment Merck
Dorzolamide: Carbonic
anhydrase inhibitor
developed via structurebased design, and ab
initio calculations
Greer, J. et al. J. Med.
Chem. 1994, 37, 1035-1054;
J. Med. Chem. 1989, 32,
2510
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Successes with Pharmacophores
ZOMIG® for Migraine
treatment - Wellcome,
Zeneca
Zolmitriptan: 5HT1agonist developed via
molecular modeling,
pharmacophore
development
Glen, R. C. et al. J. Med.
Chem. 1995, 38, 3566-3580.
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History and Evolution of ComputerAided Drug Design
60s - 70s … QSAR
focus on lead optimization
80s … Molecular Modeling
focus shifting from lead optimization to lead identification
early 90s … 3D Searching, structure-based design (de Novo
design)
focus on lead identification
late 90s … Combinatorial Chemistry, HTS
focus on multiple lead identification
00s … Rational and Combinatorial Drug Design
focus on the leads: “candidate evaluation”
Copyright © 2009 Turquoise Consulting. All Rights Reserved
401 Ki (nM)
[1]
[11]
<1 nM
[3]
[1]
[8]
[4]
[2]
[2]
[1]
[6]
[5]
[2]
1-5 nM
Predictive
ADME in Lead
Optimization
5-50 nM
[6]
[1]
[9]
[5]
[2]
[38]
[18]
[4]
[5]
[2]
[35]
[51]
[37]
[4]
[2]
[1]
50-100 nM
[6]
[5]
[9]
100-500 nM
[5]
[2]
[13]
[8]
[3]
[4]
[18]
[32]
[12]
[12]
[13]
[16]
[10]
[37]
[51]
[7]
[11]
[3]
[3]
[7]
[4]
[5]
[32]
[45]
[17]
[4]
[1]
[2]
[1]
[7]
[28]
[17]
[2]
[7]
[3]
[4]
[1]
May99
Jun99
Jul99
Sep99
Oct99
Nov99
Dec99
Jan00
Feb00
An actual lead optimization
process at Pharmacopeia Labs.
Focused libraries have been
generated to increase potency
until Nov’99.
0.5-1 uM
[2]
1-5 uM
5-10 uM
10-50 uM
Then the predictive absorption
model is also incorporated into
the lead optimization process.
The pie charts list Absorption
characteristics for each batch.
[67]
>50 uM
Aug99
Mar00
Copyright © 2009 Turquoise Consulting. All Rights Reserved
Binned Date Received
401 Ki (nM)
[1]
[11]
<1 nM
[3]
[1]
[8]
[4]
[2]
[2]
[1]
[6]
[5]
[2]
1-5 nM
Predictive
ADME in Lead
Optimization
5-50 nM
[6]
[1]
[9]
[5]
[2]
[38]
[18]
[4]
[5]
[2]
[35]
[51]
[37]
[4]
[2]
[1]
50-100 nM
[6]
[5]
[9]
100-500 nM
[5]
[2]
[13]
[8]
[3]
[4]
[18]
[32]
[12]
[12]
[13]
[16]
[10]
[37]
[51]
[7]
[11]
[3]
[3]
[7]
[4]
[5]
[32]
[45]
[17]
[4]
[1]
[2]
[1]
[7]
[28]
[17]
[2]
[7]
[3]
[4]
[1]
May99
Jun99
Jul99
Sep99
Oct99
Nov99
Dec99
Jan00
Feb00
New libraries are optimized
based on combined properties
of binding affinity as well as
predicted absorption
characteristics.
0.5-1 uM
[2]
1-5 uM
Source: Cheng, A.; Diller, D. J.;
Dixon, S. L.; Egan, W. J.; Lauri, G.;
Merz, K. M., “Data Mining of Large
Molecular Collections,” J. Comp.
Chem. 2001, 23(1), 172-183.
5-10 uM
10-50 uM
[67]
>50 uM
Aug99
Mar00
Copyright © 2009 Turquoise Consulting. All Rights Reserved
Binned Date Received
History and Evolution of ComputerAided Drug Design
60s - 70s … QSAR
focus on lead optimization
80s … Molecular Modeling
focus shifting from lead optimization to lead identification
early 90s … 3D Searching, structure-based design (de Novo
design)
focus on lead identification
late 90s … Combinatorial Chemistry, HTS
focus on multiple lead identification
00s … Rational and Combinatorial Drug Design
focus on the leads: “candidate evaluation”
Copyright © 2009 Turquoise Consulting. All Rights Reserved
In Silico Screening Strategy
for Xenobiotic Metabolism
Input:
1A2
2B6
Molecule
database
2C9
2C19
2D6
2E1
3A4
3D-QSAR models of
FMO, NAT, EH, GTs,
STs, Permeability, Caco2, Transporters etc
...
Refine model
Output:
Substrate / Interaction
probability scale
Validate with in
vitro models
From: Ekins, S. et al. Pharmacophore Perception,
Development and Use in Drug Design, Güner, O. F., Ed.,
2000, La Jolla, pp 269-288.
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Sildenafil Fitting to a Predictive
Model for CYP2D6 via Catalyst
From: Ekins, S. et al. Pharmacophore Perception,
Development and Use in Drug Design, Güner, O. F., Ed.,
2000, La Jolla, pp 269-288.
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Lead Identification & Optimization
Work-flow
Receptor Structure
Unknown
Known
Active
Leads
Unknown
Leads
known
Random
screening
Ligand-based
design
De Novo
design
Structure-based
design
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Lead Identification & Optimization
Work-flow: From Hits to Leads
Receptor Structure
Unknown
Known
None
Random
“Rational”
screening
Fast docking,
De novo design
Hits
Fast SAR
e.g., CSAR
Docking, scoring
SBF
Leads
e.g., QSAR
Pharmacophore
Precise docking,
S-B optimization
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Potential Shortcomings of CADD
Molecular Alignment is a very important
tool to help Medicinal Chemists see how
the new compound they have synthesized
relates to the known active compounds
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How do Methotrexate and Folate Align?
Methotrexate
Folic Acid
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MTX and Folic Acid Alignment
Based on Shape
Shape
alignment
with
ROCS
Flexible
alignment
with MOE
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Flexible Ligand Alignment with
Maestro
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Methotrexate and Folic Acid Bound
to DHFR
From PDB 4DFR and 1RX7
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Following the Protein Alignment
Using ‘Protein
Structure Alignment’
tool within Maestro
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Electrostatic Views – Standard
Alignment
Shape TanimotoComboScore ColorScore
0.95
1.853
-10.837
ET_pb
0.67
* ROCS was used
for alignments
* EON for electrostatic
views
ET_coul
0.668
ET_combo
1.631
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Electrostatic Views – Bound
Conformations
ET_pb
0.67
0.507
ET_coul
0.668
0.581
ET_combo
1.631
1.207
Shape TanimotoComboScore ColorScore
0.95
1.853
-10.837
0.7
1.216
-5.67
* ROCS –scoreonly
was used for alignments
* EON for electrostatic
views
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Alignment Starting with the Bound
Conformations?
Refining the bound
conformations with
default scoring
function with MOE
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Can we find the ‘true’ alignments
with standard tools?
Alignment with MOE, after increasing the
donor-acceptor score 10-fold and deleting
all other contributions to the similarity score
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Can we force alignment by cherry
picking pharmacophore features?
•Manual pharmacophore features
generated with Discovery Studio
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Automated Pharmacophore
Generation
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Challenges in Automated
Pharmacophore Alignments
•Automated pharmacophore
models generated with Phase
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Avoid Pitfalls in Pharmacophore
Alignments
Localized
pharmacophore
model does not
require the rest
of the molecule
for alignment
•Automated pharmacophore
model generated with Phase
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My Favorite Alignment
One of the surviving
alignments generated
with Phase
Acceptors
•Automated pharmacophore
model generated with Phase
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Multiple Binding Modes - MTX
H-bond
donor to
which amino
acid?
ILE94?
ILE5?
What kind of
interaction
with ASP27?
H-bond
donor?
H-bond
acceptor?
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MTX and Folic Acid within DFHR
Notice the alignment of the two blue nitrogen atoms in folate with the two red oxygen atoms in the
enzyme. These two hydrogen bonds, along with a series of interactions with bridging water
molecules (not shown), are the basis of recognition. PDB entries 1DLS and 1DHF were used for
the illustrations.
Ref: Goodsell, D.S., “The Molecular Perspective: Methotrexate,”
Stem Cells, 1999, 17(5), 314-315
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Multiple Binding Modes - Folate
1RX7
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Summary
New Medications:
save lives,
extend our life-span, and
improve our life quality
CADD is an essential aspect of drug discovery and
development
Historically, CADD has most contribution in early stage
discovery
CADD teams assume a new role in supporting discovery and
optimization of leads through various techniques:
Lead optimization
Scaffold hopping
Property calculations
Structural alignments
Library design and optimization
Hit prioritization, rank ordering
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