Drug%Discovery:%Proteomics,%Genomics%

!
Philip!E.!Bourne!(pbourne@ucsd.edu)
It%Was%the%Best%of%Times,%It%Was%the%
Worst%of%Times%

SPPS273 1/10/13%
2%
 OMICS%D%The%Best%of%
Times%

SPPS273 1/10/13%
3%
The%Worst%of%Times%

Source: http://www.pharmafocusasia.com/strategy/drug_discovery_india_force_to_reckon.htm

SPPS273 1/10/13%
4%
 Stated%Another%%
Way%
•  Glass ½ Empty: drug
discovery in the
traditional sense is in a
woeful state
•  Glass ½ Full:
–  We have an explosion of
data and hence a new
emerging understanding
of complex biological
systems
–  Information technology is
advancing rapidly
SPPS273 1/10/13%
The$Take$Home$Message$
Let%OpKmism%Rule%
•  Let optimism rule – let
IT, traditional
computational
chemistry and
cheminfomatics meet
bioinformatics, systems
biology and information
science to discover
drugs in new ways –
Systems Pharmacology
5%
Agenda%

•  Where my perspective comes from

•  The omics revolution
•  The open science & IT revolutions
•  The impact on drug discovery
•  Applying the new biology to drug discovery
–  Example 1 – Drug repositioning
–  Example 2 - Determining side-effects
•  Words of caution

SPPS273 1/10/13%
6%
 My%PerspecKve/Bias%
•  We work in the area of structural
bioinformatics & more broadly
computational biology
•  We distribute the equivalent to ¼
the Library of Congress to approx.
300,000 scientists each month
•  We are interested in improving the
drug discovery process through
computationally driven hypotheses
on the complete biological system
– systems pharmacology

•  Personally:
–  Open science advocate
–  Started 4 companies
–  Spent whole life in the ivory tower
–  AVC of Innovation & Industrial
Alliances

SPPS273 1/10/13%
7%
My$Perspec2ve/Bias$
The Omics Driver
•  DNA sequence data
are doubling every 5
months
•  Funders are
demanding data
sharing plans
•  The long tail is
neglected

On the Future of Genomic Data

Science 11 February 2011:
vol. 331 no. 6018 728-729
 Its%Not%Just%About%Numbers%its%About%Complexity%
Number of released entries"

Year"
SPPS273 1/10/13%
9%
The$Omics$Revolu2on$ Courtesy%of%the%RCSB%Protein%Data%Bank%
The OMICS Revolution in One Slide
 Metagenomics%
•  New%type%of%genomics%
•  New%data%(and%lots%of%it)%
and%new%types%of%data%–%
IniKal%ocean%survey%
–  17M%new%(predicted%
proteins!)%4D5%x%growth%
in%just%few%months%and%
much%more%coming%
–  New%challenges%and%
exacerbaKon%of%old%
challenges%

SPPS273 1/10/13%
11%
The$Omics$Revolu2on$
 Metagenomics:%Early%Results%

•  More%then%99.5%%of%DNA%in% •  Everything%we%touch%
very%environment%studied% turns%out%to%be%a%gold%
represent%unknown% mine%
organisms% •  Environments%studied:%
–  Culturable%organisms%are%
–  Water%(ocean,%lakes)%
excepKons,%not%the%rule%
–  Soil%
•  Most%genes%represent%
–  Human%body%(gut,%oral%
distant%homologs%of%known% cavity,%human%
genes,%but%there%are% microbiome)%
thousands%of%new%families%
SPPS273 1/10/13%
12%
The$Omics$Revolu2on$
 Metagenomics%New%Discoveries%
Environmental%(red)%vs.%Currently%Known%PTPases%(blue)%
1

SPPS273 1/10/13%
13%
The$Omics$Revolu2on$
 Warning:%
With%Explosive%Growth%Comes%
Problems:%
%
Currently%30%%of%FuncKonal%
AnnotaKons%in%Databases%May%be%
Wrong%

SPPS273 1/10/13%
14%
The$Omics$Revolu2on$
Agenda%

•  Where my perspective comes from

•  The omics revolution
•  The open science & IT revolutions
•  The impact on drug discovery
•  Applying the new biology to drug discovery
–  Example 1 – Drug repositioning
–  Example 2 - Determining side-effects
•  Words of caution

SPPS273 1/10/13%
15%
 Towards%Open%Science%
•  Open%access%publishing%
•  Open%source%socware%
•  GeneraKon%of%scienKsts%weaned%on%social%networks%
•  Blogs,%wikis,%social%bookmarking%etc.%are%becoming%a%
valid%form%of%scienKfic%discourse%%

hep://www.osdd.net/%

SPPS273 1/10/13%
16%
Open$Science$
 An%Exemplar%of%Open%Science%
www.sagebase.org%

SPPS273 1/10/13%
17%
Open$Science$
 The%Open%Access%Baele%is%Not%Won,%
but%its%Looking%Good%

SPPS273 1/10/13%
18%
Open$Science$
Agenda%

•  Where my perspective comes from

•  The omics revolution
•  The open science & IT revolutions
•  The impact on drug discovery
•  Applying the new biology to drug discovery
–  Example 1 – Drug repositioning
–  Example 2 - Determining side-effects
•  Words of caution

SPPS273 1/10/13%
19%
 Why Don’t we Do Better?
A Couple of Observations

•  Gene%knockouts%only%effect%phenotype%in%10D20%%
of%cases%,%why?%%
–  redundant%funcKons%%
–  alternaKve%network%routes%%
–  robustness%of%interacKon%networks%
A.L.$Hopkins$Nat.$Chem.$Biol.$2008$4:682I690$

•  35%%of%biologically%acKve%compounds%bind%to%
more%than%one%target% Paolini$et$al.$Nat.$Biotechnol.$2006$24:805–815$

SPPS273 1/10/13%
20%
Drug$Discovery$–$Some$Inconveneint$Truths$
 Why Don’t we Do Better?
A Couple of Observations
•  Tykerb – Breast cancer
•  Gleevac – Leukemia, GI
cancers
•  Nexavar – Kidney and liver
cancer
•  Staurosporine – natural product
– alkaloid – uses many e.g.,
antifungal antihypertensive

Collins%and%Workman%2006%Nature$Chemical$Biology$2%689D700%

SPPS273 1/10/13%
21%
Drug$Discovery$–$Some$Inconvenient$Truths$
 ImplicaKons%
•  Ehrlich s%philosophy%of%magic%bullets%targeKng%
individual%chemoreceptors%has%not%been%realized%

•  Stated%another%way%–%The%noKon%of%one%drug,%one%
target,%one%disease%is%a%liele%naïve%in%a%complex%
system%

SPPS273 1/10/13%
22%
Drug$Discovery$–$Some$Inconvenient$Truths$
Agenda%

•  Where my perspective comes from

•  The omics revolution
•  The Open Science & IT revolutions
•  The impact on drug discovery
•  Applying the new biology to drug discovery
–  Example 1 – Drug repositioning
–  Example 2 - Determining side-effects
•  Words of caution

SPPS273 1/10/13%
23%
 What%if…%
•  We%can%characterize%a%proteinDligand%
binding%site%from%a%3D%structure%
(primary%site)%and%search%for%that%site%
on%a%proteome%wide%scale?%

•  We%could%perhaps%find%alternaKve%
binding%sites%(offDtargets)%for%exisKng%
pharmaceuKcals%and%NCEs?%

SPPS273 1/10/13%
24%
Systems$Pharmacology$–$Example$from$Our$Lab$
 What%Do%These%OffDtargets%Tell%Us?%

•  PotenKally%many%things:%
1.  Nothing%
2.  How%to%opKmize%a%NCE%
3.  A%possible%explanaKon%for%a%sideDeffect%of%a%drug%
already%on%the%market%
4.  A%possible%reposiKoning%of%a%drug%to%treat%a%
completely%different%condiKon%
5.  The%reason%a%drug%failed%%
6.  A%mulKDtarget%strategy%to%aeack%a%pathogen%
%

SPPS273 1/10/13%
25%
Systems$Pharmacology$–$Example$from$Our$Lab$
 Need%to%Start%with%a%3D%DrugDReceptor%Complex%
D%The%PDB%Contains%Many%Examples%
Generic Name Other Name Treatment PDBid

Lipitor Atorvastatin High cholesterol 1HWK, 1HW8…

Testosterone Testosterone Osteoporosis 1AFS, 1I9J ..

Taxol Paclitaxel Cancer 1JFF, 2HXF, 2HXH

Viagra Sildenafil citrate ED, pulmonary 1TBF, 1UDT,

arterial 1XOS..
hypertension

Digoxin Lanoxin Congestive heart 1IGJ

failure

26

Systems$Pharmacology$–$Example$from$Our$Lab$
 A!Reverse!Engineering!Approach!to!
!Drug!Discovery!Across!Gene!Families!
Characterize%ligand%binding%% IdenKfy%offDtargets%by%ligand%%
site%of%primary%target%% binding%site%similarity%
(Geometric%PotenKal)% (Sequence%order%independent%%
profileDprofile%alignment)%
Extract%known%drugs%% %
or%inhibitors%of%the%%
primary%and/or%offDtargets%

Search%for%similar%
small%molecules% …%

Dock%molecules%to%both%%
primary%and%offDtargets%

Xie%and%Bourne%2009%%
Bioinforma2cs$25(12)$305I312%
StaKsKcs%analysis%%
of%docking%score%%
correlaKons%
27

Systems$Pharmacology$–$Example$from$Our$Lab$
Agenda%

•  Where my perspective comes from

•  The omics revolution
•  The open science & IT revolutions
•  The impact on drug discovery
•  Applying the new biology to drug discovery
–  Example 1 – Drug repositioning
–  Example 2 - Determining side-effects
•  Words of caution

SPPS273 1/10/13%
28%
 The%Problem%with%Tuberculosis%
•  One third of global population infected
•  1.7 million deaths per year
•  95% of deaths in developing countries
•  Anti-TB drugs hardly changed in 40 years
•  MDR-TB and XDR-TB pose a threat to
human health worldwide
•  Development of novel, effective, and
inexpensive drugs is an urgent priority

SPPS273 1/10/13%
29%
Example$1$–$Reposi2oning$The$TB$Story$
Looking%at%the%Problem%on%a%Large%
Scale%

SPPS273 1/10/13%
30%
 1. Determine the TB Structural Proteome
Kinnings et al 2010 PLoS Comp Biol 6(11): e1000976

3,%996% 2,%266% 284%

1,%446%

•  High quality homology models from ModBase (http://

modbase.compbio.ucsf.edu) increase structural
coverage from 7.1% to 43.3%
A Multi-target/drug Strategy
 2. Determine all Known Drug
Binding Sites in the PDB
•  Searched the PDB for protein crystal structures
bound with FDA-approved drugs
•  268 drugs bound in a total of 931 binding sites

140%
No. of drugs

120%
Acarbose%
100%
Darunavir% AlitreKnoin%
80%
Conjugated%
60% estrogens%
40%
Chenodiol%
Methotrexate%
20%

0%
1% 2% 3% 4% 5% 6% 7% 8% 9% 10%11%12%13%14%15%16%17%18%19%20%21%22%23%24%25%26%27%28%29%30%31%32%33%34%35%36%37%

No.%of%drug%binding%sites%
A Multi-target/drug Strategy
Map 2 onto 1 – The TB-Drugome
http://funsite.sdsc.edu/drugome/TB/

Similarities between the binding sites of M.tb proteins (blue),

and binding sites containing approved drugs (red).
 Summary%of%the%TB%Story%

•  Entacapone%and%tolcapone%shown%to%have%potenKal%for%
reposiKoning%
•  Direct%mechanism%of%acKon%avoids%M.$tuberculosis%
resistance%mechanisms%
•  Possess%excellent%safety%profiles%with%few%side%effects%–%
already%on%the%market%
•  In$vivo$support%
•  Assay%of%direct%binding%of%entacapone%and%tolcapone%to%
InhA%reveals%a%possible%lead%with%no%chemical%relaKonship%
to%exisKng%drugs%

SPPS273 1/10/13%
34%
Example$1$–$Reposi2oning$The$TB$Story$ Kinnings%et%al.%2009%PLoS$Comp$Biol$5(7)%e1000423%
 Summary from the TB Alliance –
Medicinal Chemistry

•  The%minimal%inhibitory%concentraKon%(MIC)%of%260%
uM%is%higher%than%usually%considered%
•  MIC%is%65x%the%esKmated%plasma%concentraKon%
•  Have%other%InhA%inhibitors%in%the%pipeline%

SPPS273 1/10/13%
35%
Example$1$–$Reposi2oning$The$TB$Story$ Kinnings%et%al.%2009%PLoS$Comp$Biol$5(7)%e1000423%
New%Ways%of%Thinking%

•  Polypharmacology%–%One%or%mulKple%drugs%binding%
to%mulKple%targets%for%a%collecKve%effect%aka%Dirty$
Drugs$

•  Network$Pharmacology$–%Measuring%that%effect%on%
the%whole%biological%network%

SPPS273 1/10/13%
36%
Agenda%

•  Where my perspective comes from

•  The omics revolution
•  The Open Science & IT revolutions
•  The impact on drug discovery
•  Applying the new biology to drug discovery
–  Example 1 – Drug repositioning
–  Example 2 - Determining side-effects
•  Words of caution

SPPS273 1/10/13%
37%
 SPPS273 1/10/13%
38%
Example$2$I$The$Torcetrapib$Story$ PLoS$Comp$Biol$$2009$%5(5)%e1000387%
 Cholesteryl!Ester!Transfer!Protein%(CETP)%%

CETP%inhibitor%

X
CETP%

LDL% HDL%
Bad%Cholesterol% Good%Cholesterol%

SPPS273 1/10/13%
39%
Example$2$I$The$Torcetrapib$Story$ PLoS$Comp$Biol$$2009$%5(5)%e1000387%
Systems
Pharmacology
Enzyme
inhibition
Uptake ××

× × ×

×
Systemic ×
response
Catalytic Secretion
(or biomass
site components)

Affect protein
Metabolic
function network

Target binding
Drug molecules
Slide from Roger Chang
 Multiscale Modeling of Drug
Actions
Understanding of Prediction of molecular
dynamics and interaction network on
kinetics of protein- a genome scale
ligand interactions

Traditional
Approach
physiological!!process!

Reconstruction,
Knowledge analysis and
representation simulation of
and discovery & biological networks
model integration
Systems-based
Approach
Motivators
 ModificaKons%to%Early%Stage%Drug%Discovery%

OffDtargets% Systems%Approach%
SPPS273 1/10/13%
42%
hep://www.celgene.com/images/celgene_drug_arrow.gif%
Agenda%

•  Where my perspective comes from

•  The omics revolution
•  The Open Science & IT revolutions
•  The impact on drug discovery
•  Applying the new biology to drug discovery
–  Example 1 – Drug repositioning
–  Example 2 - Determining side-effects
•  Words of caution

SPPS273 1/10/13%
43%
Words%of%CauKon%

•  Mistrust%of%computaKonal%approaches%

•  BioinformaKcs%was%previously%oversold%

•  Omics%was%previously%oversold%

•  Openness%is%an%alien%culture%to%drug%
discovery%
SPPS273 1/10/13%
44%
Further%Reading%
•  L.%Xie,%L.%Xie,%S.L.%Kinnings%and%P.E.%Bourne%2012%
Novel%ComputaKonal%Approaches%to%
Polypharmacology%as%a%Means%to%Define%Responses%
to%Individual%Drugs,%Annual$Review$of$Pharmacology$
and$Toxicology%52:$361D379%[PDF].%
•  And%references%therein%

SPPS273 1/10/13%
45%
 pbourne@ucsd.edu-
!

QuesKons?%
SPPS273 1/10/13%
46%