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Structural Bioinformatics in Drug Discovery
Melissa Passino
Structural BioinformaticsStructural Bioinformatics
• What is SBI?“Structural bioinformatics is a subset of bioinformatics concerned with the use of biological structures – proteins, DNA, RNA, ligands etc. and complexes thereof to further our understanding of biological systems.”
http://biology.sdsc.edu/strucb.html
SBI in Drug Design and DiscoverySBI in Drug Design and Discovery
• SBI can be used to examine:• drug targets (usually proteins)• binding of ligands
↓
“rational” drug design
(benefits = saved time and $$$)
Traditional Methods of Drug DiscoveryTraditional Methods of Drug Discovery
natural (plant-derived)
treatment for illness/ailments
↓
isolation of active
compound(small, organic)
synthesisof compound
↓
manipulation of structure to get
better drug(greater efficacy, fewer side effects)Aspirin
Modern Methods of Drug DiscoveryModern Methods of Drug Discovery
What’s different?
• Drug discovery process begins with a disease (rather than a treatment)
• Use disease model to pinpoint relevant genetic/biological components (i.e. possible drug targets)
Modern Drug DiscoveryModern Drug Discovery
disease → genetic/biological target
↓
discovery of a “lead” molecule- design assay to
measure function of target- use assay to look for
modulators of target’s function
↓high throughput screen (HTS)
- to identify “hits” (compounds with binding in low nM to low μM range)
Modern Drug DiscoveryModern Drug Discovery
small molecule hits↓
manipulate structure to increase potency i.e. decrease Ki to low nM affinity
↓
*optimization of lead molecule into candidate drug*
fulfillment of required pharmacological properties:potency, absorption, bioavailability, metabolism, safety
↓
clinical trials
Interesting facts...Interesting facts...
• Over 90% of drugs entering clinical trials fail to make it to market
• The average cost to bring a new drug to market is estimated at $770 million
Impact of Structural BioinformaticsImpact of Structural Bioinformatics on Drug Discovery on Drug Discovery
• Speeds up key steps in DD process by combining aspects of bioinformatics, structural biology, and structure-based drug design
Bio-informatics
Structure-based Drug Design
Structural Biology
Fig 1 & 2
Fauman et al.
Identifying Targets: Identifying Targets: The “Druggable Genome”The “Druggable Genome”
human genome
polysaccharides
lipids nucleic acids proteins
Problems with toxicity, specificity, and difficulty in creating potent inhibitors
eliminate the first 3 categories...
human genome
polysaccharides
lipids nucleic acids proteins
proteins with binding site
“druggable genome” = subset of genes which express proteins capable of binding small drug-like molecules
Relating druggable targets Relating druggable targets to disease...to disease...
GPCR
STY kinases
Zinc peptidases
Serine proteases
PDE
Other 110 families
Cys proteases
Gated ion-channel Ion channels
Nuclear receptor
P450 enzymes
Analysis of pharm industry reveals:
• Over 400 proteins used as drug targets
• Sequence analysis of these proteins shows that most targets fall within a few major gene families (GPCRs, kinases, proteases and peptidases)
Fig. 3, Fauman et al.
Assessing Target DruggabilityAssessing Target Druggability
• Once a target is defined for your disease of interest, SBI can help answer the question:
Is this a “druggable” target?
• Does it have sequence/domains similar to known targets?
• Does the target have a site where a drug can bind, and with appropriate affinity?
Other roles for SBI in drug discoveryOther roles for SBI in drug discovery
• Binding pocket modeling
• Lead identification• Similarity with known
proteins or ligands
• Chemical library design / combinatorial chemistry
• Virtual screening
• *Lead optimization*• Binding• ADMET
SBI in cancer therapy:SBI in cancer therapy:MMPIsMMPIs
• Inability to control metastasis is the leading cause of death in patients with cancer (Zucker et al. Oncogene. 2000, 19, 6642-6650.)
• Matrix metalloproteinase inhibitors (MMPIs) are a newer class of cancer therapeutics
• can prevent metastasis (but not cytotoxic); may also play role in blocking tumor angiogenesis (growth inhibition)
• Used to treat “major” cancers: lung, GI, prostate
What is an MMP?What is an MMP?
• Family of over 20 structurally related proteinases
• Principal substrates:• protein components of extracellular matrix
(collagen, fibronectin, laminin, proteoglycan core protein)
• Functions:• Breakdown of connective tissue; tissue
remodeling
• Role in cancer:• Increased levels/activity of MMPs in area
surrounding tumor
Brown PD. Breast Cancer Res Treat 1998, 52, 125-136.
Whittaker et al. Chem. Rev. 1999, 99, 2735-2776
MMP-1,3,8
MMP-2
MMP-7
MMP-9
MMP-10 to 13,19,20
MMP-14
to 17Whittaker et al. Chem. Rev. 1999, 99, 2735-
2776
Whittaker et al. Chem. Rev. 1999, 99, 2735-
2776
“metallo” in MMP = zinc
→ catalytic domain contains 2 zinc atoms
MMP catalysisMMP catalysis
Peptidic inhibitorsPeptidic inhibitors
• Structure based design – based on natural
substrate collagen– zinc binding group
• Poor Ki values, not very selective (inhibit other MPs)
Brown PD. Breast Cancer Res Treat 1998, 52, 125-136.
Peptidic hydroxamate inhibitorsPeptidic hydroxamate inhibitors
• Specificity for MMPs over other MPs
• Better binding (low nM Ki)
• But poor oral bioavailability
A (not very) long time ago, in a town (not too) far
away……lived a company named Agouron…
…and this company had a dream, a
dream to design a nonpeptidic
hydroxamate inhibitor of MMPs…
...so they made some special crystals…
used x-ray crystallography/3D
structure of recombinant human
MMPs bound to various inhibitors
↓to determine key a.a.
residues, ligand substituents needed
for binding Gelatinase A
http://www.rcsb.org/pdb/
…and used the magic of structural bioinformatics to design many, many
nonpeptidic hydroxylates.
oral bioavailabityK i
anti-growth
anti-metastasis
repeat…
Results…Results…
AG3340 “Prinomastat”
• Good oral bioavailability
• Selective for specific MMPs – may implicate their
roles in certain cancers
PrinomastatPrinomastat
• Evidence showing prevention of lung cancer metastasis in rat and mice models
• Clinical trials
→ non small cell lung cancer
→ hormone refractory prostate cancer…stopped at Phase 3 (Aug 2000) because did not show effects against late stage metastasis
Morals of the story…Morals of the story…
• SBI can be used as basis for lead discovery and optimization
• MMPs are good targets for chemotherapy to help control metastasis…
…but MMPIs must be combined with other cytotoxic drugs to get maximum benefits, and used at earliest stage possible
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