DRUG DISCOVERY & GRID COMPUTING

Habibah A Wahab, PhD

School of Pharmaceutical Sciences,
Universiti Sains Malaysia

Biosciences WG, PRAGMA 12, March 2007

 Opportunity For Computer Scientist
in Pharma Industries
• Ranks among the fastest growing manufacturing industries.
• More than 6 out of 10 workers have a bachelor’s, master’s,
professional, or Ph.D. degree—twice the proportion for all
industries combined.
• Fifty-nine percent of all jobs are in large establishments
employing more than 500 workers.
• Earnings are much higher than in other manufacturing
industries.
• Provided 291,000 wage and salary jobs in 2004.
• Nearly 60 percent of this industry’s jobs in 2004 were in
establishments that employed more than 500 workers.

Biosciences WG, PRAGMA 12, March 2007

 Outlook for computer scientists
in pharmaceutical industries

• Computer specialists such as

systems analysts, biostatisticians,
and computer support specialists
also will be in demand as disciplines
such as biology, chemistry, and
electronics continue to converge and
become more interdisciplinary,
creating demand in rapidly emerging
fields such as bioinformatics and
nanotechnology.

Biosciences WG, PRAGMA 12, March 2007

 DRUG DISCOVERY
Post-clinical
Discovery Phase Preclinical PhaseClinical PhasePhase

Clinical
Disease /
Target Lead Lead Safety
Target PreClinical PostClinical
Validation Identification Optimisation &
Identification
Efficacy

Big Pharma/ Outsource to Small Big Pharma

Companies

•Lengthy and expensive:

•10 – 15 Years; USD 800 – 1 billion
•Out of 5000 medicine tested, 5 reach clinical trial (Pharmaceutical
Research & Manufacturer of America)
•Out of 5, 1 reach market (Tufts Center of Research on Drug
Development)
•Delay can cost $4-5 million/day.
•Multidisciplinary Efforts involving individuals, partnerships,
corporations, government agencies, manufacturer, scientific
institutions.
Biosciences WG, PRAGMA 12, March 2007
 Source of Drugs
• Drugs are derived from the following two main
sources:
– Natural Product:
• From plant parts or products. Seeds, stem, roots, leaves, resin, and
other parts yield these drugs. Examples, salicylic acid, digitalis,
vincristine and opium.
• From animal sources: Glandular products from animals are used,
such as insulin and thyroid.
• Marine organisms:
• Microorganisms: Penicillin, erythromycin
• Mineral sources: Some drugs are prepared from minerals, for
example, potassium, chloride, and lithium carbonate (an
antipsychotic).

– Synthetic sources:
• Frequently this can eliminate side effects and increase the potency
of the drug. Examples include barbiturates, sulfonamides, and
aspirin.

Biosciences WG, PRAGMA 12, March 2007

Virtual Screening to Find Hit/Lead

Biosciences WG, PRAGMA 12, March 2007

 Virtual Screening

• Usually employ docking computation

as it gives detailed representation of
binding site

Biosciences WG, PRAGMA 12, March 2007

 Phases of a pharmaceutical development

Molecular Docking: Predict how small molecules, such as

substrates or drug candidates, bind to a receptor of known 3D
structure
Target discovery Lead discovery

Target Lead Pre- & Clinical

Target Lead Phases (I-III)
Identification Validation Identification Optimization

Database
Alignment QSAR
filtering
Similarity Computer Aided
Biophores ADMET Drug Design
analysis
(CADD)
diversity Combinatorial de novo
vHTS
selection libraries design

Biosciences WG, PRAGMA 12, March 2007

 NaPIMM©
Natural Product Information and Molecular
Modelling (NaPIMM) Portal

Biosciences WG, PRAGMA 12, March 2007

 INTRODUCING NAPIMm©

• COMPUTATIONAL PLATFORM
– Grid enabled molecular modelling platform
– Automatic docking & reverse docking server
– MD simulation server
– Protein-structure prediction server
• DATABASE SYSTEM: NADI©
– NADI-CHEM©
– MNATCHEM©
– NADI-RA©
– NADI-HERBS©

Biosciences WG, PRAGMA 12, March 2007

 NaDI©: Features
• COPYRIGHTED DATABASE SYSTEM
• Comprehensive 3D chemical structure
Database of natural products
– Inclusive of chemical properties and biological
activities references
– 2D structures
– 3D structures ready for in silico drug screening
• Drug Receptor Database –
– provide drug receptor and disease information.
– 3D structure of drug target
• Herbal Monographs
– Comprehensive description about traditional
uses of Malaysian and Chinese medicinal
plants Biosciences WG, PRAGMA 12, March 2007
Biosciences WG, PRAGMA 12, March 2007
 WHY NaPIMM ?
• Malaysia has 12,000 flowering species
plants (10% already known for medicinal
values).
• Analysis of compounds isolated from
natural products showed that most of
them are not available in chemical
database.
• Research experience in molecular
modelling of natural products on :
– Xanthine oxidase
– protein tyrosine kinase receptor.
– Dihydrofolate reductase, etc.
• DOCK AROUND THE CLOCK
• Biosciences WG, PRAGMA 12, March 2007
DRUG DISCOVERY USING NAPIMM©

Database Database
Design Content Enzyme
(Receptor Development in silico Inhibition
& (Receptor studies (in vitro
Small Molecule & assay)
Small Molecule

Bioinformatics Molecular Modelling Validation

(Physical (non-real/simplified) system that
mimics biological/chemical system)

Biosciences WG, PRAGMA 12, March 2007

 Docking Workflow in NAPIMm

3 D Structure Optimised
literature 2 D Structure 3 D Structure &
(Target & Partial charge
(Target & Ligand) (ligand)
Ligand) assignment

In NADI DATABASES

AutoDock
Grid & GPF & DPF
Ranking
Docking setup

AUTOMATED, GENERATED WITHIN

MMSERVER

Biosciences WG, PRAGMA 12, March 2007

 Source of datasets

• Available database; usually known

chemicals
– Commercial, Daylight, Cambridge CSD, MDL
etc
– Public domain e.g. ZINC, NCI, PubChem
• Totally virtual compounds generated by
computers (either has existed or yet to be
existed).
• Or build one yourself; perhaps a dedicated
one like natural product database

Biosciences WG, PRAGMA 12, March 2007

Natural Products: Facts

Plants Extracts Fractions Chemicals

H3C CH3

O
O

H3C OAc
H3C CH3
H2N OH
H3C
H3C O

Norcarotenoid CH3
O

Jaspine B
OSO
OH 3

OH

HN O H
HN
NH NH
3

2
2

OH
H

squalamine
O CH3

Jaspine A

Biosciences WG, PRAGMA 12, March 2007

Natural Products: Drug Source

Biosciences WG, PRAGMA 12, March 2007

 Natural Products: Drug Source
• 65% drugs exist today originally derived from
natural sources.

• E.g. digitalis, aspirin and paclitaxel (Taxol)

• “natural products are biologically validated

starting points for library design”.

• Synthesised/modified by proteins – highly likely to

bind to proteins having similar folds.

Biosciences WG, PRAGMA 12, March 2007

Biosciences WG, PRAGMA 12, March 2007
 Cluster D
Ac
ce

and uploaded to Hawk

Output files generated
docking jobs on each
ss

from Hawk and run

file

Receive input files

assigned nodes
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Receive input files from Hawk and Submit input files and distribute jobs to
run jobs on each assigned nodes several clusters on Grid environment

Cluster C Output files generated and un Process ligand input file, create parameter Hawk server –
r Malaysia
uploaded to Hawk n d es O files & shell script files
a od Re ut (hawk.usm.my)
a wk d n ru ce
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m ig do ive oa s
f ro ass nd ck inp
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fil ac ed g tf d ne
p ut n e rat wk jo ile to ra
in s o ne Ha bs s H ted
ve b g e no on fro aw
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to de e m k and
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Grid environment
Cluster B Cluster A
Biosciences WG, PRAGMA 12, March 2007
 NaPIMM CASE STUDY

Screening of flavonoids on Dengue-2

Protease

Biosciences WG, PRAGMA 12, March 2007

 Dengue
• Dengue is a serious infectious disease that is endemic in over 100
countries.
• An estimated of 50 million infection per year globally with more
than 2.5 billion people are at risk for epidemic transmission.
• Major affected regions are the south-east Asia and the western
Pacific (increasing reports of this disease in the Americas).
• Caused by the dengue virus which is a member of the Flaviviridae.
• Spread by the highly domesticated Aedes aegypti mosquito.
• Dengue can be classified into:
– Dengue Fever (DF)
• a flu-like illness with symptoms like fever, headaches, joint aches and
rashes
– Dengue Haemorrhagic Fever (DHF).
• more severe and often fatal complication of DF as a result of the dengue
shock syndrome (DSS).
• To date, no licensed vaccine or therapeutic drug available for DF
and DHF/DSS, although there have been reports of some vaccine
candidates in clinical trials.
• The treatment for DF and DHF/DSS has only been supportive thus
far. Biosciences WG, PRAGMA 12, March 2007
 Flavonoids
• Flavonoids belong to a class of chemical
compounds that are ubiquitous in the
OH
vegetable kingdom with about 6000
structures of flavonoids are known. OH

O
• Among the most widely studied flavonoids HO
is quercetin (Fig. 1) which is present
widely in vegetables and fruits, with a OH
daily intake of up to 25 mg/day in a
OH O
normal human diet.
The chemical structure of quercetin
• Most flavonoids are known to be a
powerful antioxidant that can scavenge
the reactive oxidative species and a
potent chemopreventive agent.
• Now, we would like to see whether it has
anti-dengue activity
Biosciences WG, PRAGMA 12, March 2007
Screening of flavonoids on Dengue-2 Protease

Biosciences WG, PRAGMA 12, March 2007

Screening of flavonoids on Dengue-2
Protease

Biosciences WG, PRAGMA 12, March 2007

Screening of flavonoids on Dengue-2
Protease

B. rotunda (1)
B. rotunda (2)
B. rotunda (3)

Biosciences WG, PRAGMA 12, March 2007

 WHAT’S NEXT

• We are very interested to further develop AMEXg,

MMServer on GridSphere
• Further develop NAPIMm so that it fully utilise
Grid Computing – current test only involve 4
PRAGMA sites.
• To incorporate Quantum Chemical Calculation
and Cheminformatics application within NAPIMm
• Use NAPIMm for PRAGMA real science project
• Have PRIUS students in USM to help us achieving
above.

Biosciences WG, PRAGMA 12, March 2007

 Sipadan Island, Sabah, Malaysia

I would like to thank all system administrators within PRAGMA

community especially:
Nguyen Viet Han dr Vietnam, IOIT
Eduardo Murrieta León, Mexico, malicia cluster
Yusuke Tanimura, Japan, AISTX cluster

Biosciences WG, PRAGMA 12, March 2007

Acknowledgement

Academic Collaborators Postgraduates:

 Dr. Nornisah Mohamed
 Dr. Rashidah Abdul Rahim
 Professor Noorsaadah Abdul
Rahman
 Professor Nazalan Najimudin
 Dr. Razip Samian
 Dr. Chan Huah Yong
 Professor Janez Mavri
 Professor Tom Scior
 Dr. Stephen Doughty
 Dr. Andre Aubry
 Dr. Regis Venderesse
 Dr. Bridget Jamart
 Belal O Najjar (MSc Candidate)
 Nur Hanani Che Mat
 Choong Yee Siew
 Choy Sy Bing
 Ezatul Ezleen Kamarulzaman
 Imtiaz Khalid
 Ismail Mohd Shah
 Nurul Bahiyyah Ahmad Khairudin
 Yam Wai Keat
 Suriyati Muhamad

Biosciences WG, PRAGMA 12, March 2007