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Jan, 2006 CBIS Conference 1
Shape SignaturesShape Signatures: :
NextNext--Generation Drug Discovery ToolGeneration Drug Discovery Tool
Bill WelshBill Welsh
UMDNJUMDNJ--Robert Wood Johnson Medical SchoolRobert Wood Johnson Medical School
Piscataway, NJ
Voice: (732) 235-3234
Email: [email protected]
Jan, 2006 CBIS Conference 2
Overview of TechnologiesOverview of TechnologiesComputational Tools• Rational (Computer-Aided) Drug Design• Predictive Toxicology
Small Molecules• Therapeutic Areas: pain, cancer, infectious diseases
Materials and Polymers• Biomaterials• Drug Delivery
Jan, 2006 CBIS Conference 3
Synergistic Informatics ApproachesSynergistic Informatics ApproachesReceptor-based Approaches
Ligand-based Approaches
Database Mining,Pattern Recognition
Drug Discovery
Predictive Toxicology
Jan, 2006 CBIS Conference 4
Drug Discovery ParadigmDrug Discovery Paradigm
Seamless Integration of Critical TechnologiesSeamless Integration of Critical Technologies
BiologyMedicinalChemistry
InformaticsChemicalLibraries
Jan, 2006 CBIS Conference 5
Our Integrated Discovery PlatformOur Integrated Discovery Platform
In Silico Design: Fast, Economical
Refined Hits
Time/Cost Intensive
Tests onanimal models
Most Promising Molecules
Laboratory Tests
Chemical Synthesis
Biological Assays
IND
Initial Hits
Protein receptorstructure
Known bioactive molecule
In Silico Screening• Receptor Docking• Predicted Binding Affinity• Drug-like Filters (Lipinski)• ADME/Tox screens• Database Mining• Virtual mutations
Shape SignaturesChemical Library
Jan, 2006 CBIS Conference 6
Shape SignaturesShape SignaturesSTART
OH
OH
Small molecule or Protein binding pocket
PROCESSING
Ray tracing to generate the raw data
OUTPUT
1D and 2D Shape Signatures
Shape (1D)
Shape + Charge (2D)
Diff = 0.0220
0.02
0.04
0.06
0.08
0.1
0.12
0.14
0.16
0.18
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5
0
0.020.04
0.060.080.1
0.12
0.140.16
0.180.2
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5
Shape Signatures TechnologyShape Signatures Technologymolecules are compared by subtracting their histograms
Small Diff value means that two molecules have similar
biorelevant properties
Shape SignaturesChemical Library
3+ million compounds
PF
O
CH3OCHCH3
CH3
PF
O
CH3OCH
CH3
C(CH3)3
Sarin
Soman
Jan, 2006 CBIS Conference 8
Searchable Shape Signatures Databases• 3+ million vendor available drug-like compounds• Directed libraries for kinases, NRs, GPCRs• Thematic libraries for indoles, pyrimidines, triazoles, etc• 40,000 Natural Products• 5,000 ligands extracted from Protein Data Bank (PDB)
Molecular Sketcher
Molecular Viewer
Shape SignaturesShape Signatures Software ToolSoftware Tool
& Chemical Databases& Chemical Databases
Ray Tracing
Histogram
Database Searching
Jan, 2006 CBIS Conference 9
Extract Ligands
~35K high quality crystal structures(resolution < 2.5 Å)
Preliminary Ligand Database
QueryMolecule
2D or 3D structure
List of Hits With high similarity to query
• drug-like features (Lipinski)• parent protein ID, structure, link• protein functionality• pathway info
Potential Drug Leads
FilterRemove metal ions,
salts, redundant structures
Final LigandDatabase
PDB-extractedShape Signature
Database~5,000 ligands
Convert to ShapeSig
Jan, 2006 CBIS Conference 10
Shape Signatures Database of PDB-extracted ligands
PDBPDB--extracted extracted LigandsLigandsNovel Discovery PlatformNovel Discovery Platform
Species/Protein Family
Protein Structure
Protein Data Bank (PDB): World Repository of 35,000 Protein Crystal Structures
Jan, 2006 CBIS Conference 11
Molecules Target Protein MechanismMolecules Target Protein Mechanism
0
0.02
0.04
0.06
0.08
0.1
0.12
0.14
0.16
0.18
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5
Query Molecule
Matching PDB Ligands
Target Proteins
Shape Sigs PDB Ligands Protein’s Binding Site
Public Databases
Links to Biological Pathways
0
0.02
0.04
0.06
0.080.1
0.12
0.14
0.16
0.18
0.2
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 50
0.02
0.04
0.06
0.080.1
0.12
0.14
0.160.18
0.2
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 50
0.02
0.04
0.06
0.080.1
0.12
0.140.16
0.18
0.2
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5
0
0.02
0.04
0.06
0.080.1
0.12
0.14
0.160.18
0.2
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5
Jan, 2006 CBIS Conference 12
Medical CountermeasuresMedical CountermeasuresNovel Molecules for Detection, Diagnosis,
Prevention, and Treatment of CWAs & BWAs
Searchable Molecular Libraries Automated
Drug Design
New Drug Candidates CWA/BWA Target Mapping
PF
O
CH3OCHCH3
CH3
0
0.02
0.04
0.06
0.08
0.1
0.12
0.14
0.16
0.18
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5
Jan, 2006 CBIS Conference 13
Broad ApplicabilityBroad Applicability
Therapeutics and Prophylactics
Diagnostic Agents
Medical Countermeasures
Agricultural Goods
Veterinary Medicine
Drug Delivery Systems
Shape Signatures for Discovery Shape Signatures for Discovery
of Novel Antiof Novel Anti--parasitic Agentsparasitic Agents
Case StudyCase Study
Jan, 2006 CBIS Conference 15
Intracellular Parasitic DiseasesIntracellular Parasitic Diseases
• Cause acute & chronic GI distress (diarrhea) in humans and animals; life threatening; endemic
• Serious threat to warfighter stationed in endemic regions
• Examples: malaria, toxoplasmosis**, cryptosporidiosis**, cyclosporiasis**, many others
• Highly contagious & infectious; direct contact, insects, waterborne; resistant to disinfectants (bleach)
• No vaccines, and drugs are either non-existent, inadequate, or induce parasite resistance
* NIAID * NIAID BiodefenseBiodefense Category B pathogensCategory B pathogens
Jan, 2006 CBIS Conference 16
Infectious Parasitic DiseasesInfectious Parasitic Diseases
X-ray Crystal Structure of MTIP-
MyoA Complex
Bosch J et al; PNAS (2006)
• Holy Grail: Block parasite invasion of host
• Invasion of host cells by parasite requires
interaction of two proteins (Myosin A and MTIP)
• This interaction is unique to, and universal
among, all of these parasites
• Myosin-MTIP Inhibitors
broad-spectrum activity against all species
high specificity for parasite over host
parasitic resistance virtually impossible
applicable for prophylaxis and therapy
Our SolutionOur Solution
Jan, 2006 CBIS Conference 17
Computational Design StrategyComputational Design StrategyHydrophobic-1
Hydrophobic-2
Hydrophobic-3
Donor/Acceptor
4.29±2
6.24±1
5.41
±1
9.31±2
Shape SignaturesChemical Library
3+ million compounds
Initial Hits
Priority List1 …2 …3 …4 ………
Extract Extract PharmacophorePharmacophore
Docking of HitsDocking of Hits
MTIP-Myosin A complex
ScreenScreenShape Shape SigsSigs
LibraryLibrary
Jan, 2006 CBIS Conference 18
0
0.02
0.04
0.06
0.08
0.1
0.12
0 1 2 3 4 5 6 7 8 9 10
0
0.02
0.04
0.06
0.08
0.10.12
0.14
0 1. 5 3 4. 5 6 7. 5 9 10 .5 12
00.020.040.060.080.1
0.120.140.16
0 1 2 3 4 5 6 7 8 9 10
Family of MTIPFamily of MTIP--Myosin InhibitorsMyosin Inhibitors
0
0.02
0.04
0.06
0.08
0.1
0.12
0.14
0.16
0 1 2 3 4 5 6 7 8 9
10
Shape SignaturesChemical Library
3+ million compounds
Transform of Data 1:Transformed data
100 101 102 103 104 1050
25
50
75
100
125416140312
nM compd
%gr
owth
SW416: IC50 = 75 nM
Family of Inhibitors
Drug-likeFilters
Convert to Shape Signature
Jan, 2006 CBIS Conference 19
SummarySummaryAided by Shape Signatures, we have discovered a family of potent MTIP-myosin inhibitors
Exhibit low nM inhibitory activity against P falciparum, including multi-drug resistant strains
Block invasion of erythrocytesLethal to parasite
Attractive drug-like properties: low MW, soluble, achiral, easy synthesis
Non-toxic in mice (MTD > 100 mg/kg)
Efficacy studies in mice indicate prophylactic and therapeutic activity
In vivo studies vs other familial parasites are scheduledToxoplasma, Cryptosporidium, Cyclospora, Babesia, Eimeria
May represent a breakthrough as broad-spectrum orally active prophylactic and therapeutic agents, with minimal chance of parasite resistance
For more details, visit: www.snowdonpharma.com
Jan, 2006 CBIS Conference 20
Shape Signatures: Discovery of Anthrax LF InhibitorsShape Signatures: Discovery of Anthrax LF Inhibitors
ID Structure Source Docking Score
% Inhibition(10 μM)
QUERYNSC 12155
(known inhibitor)
NIH-NCI 33 95
QUERYLFI
(known inhibitor)
Merck 39 -
-- S503428 42 99
-- G626310 38 95
-- B788321 36 96
-- HT4369 36 94
NNH
O
HO
NH2 N N
NS
NH
O
OO
OHN
O
OOH
HN
NN
N
N
N
NH2HN
O
HN
N
NH2
OHN
O NH
OH
S
O
OF
S503428 docked in the ligand binding pocket of anthrax LF
HIS686
ASP735
S503428
SER655Zn
HIS686
ASP735
S503428
SER655Zn
In Vitro Activity
Jan, 2006 CBIS Conference 21
Fastscreens large databases in secs
Extensibleworks with any kind or
number of molecular species
Innovativeexcels at scaffold hopping
Powerfulenables automated ligand design
Shape SignaturesShape Signatures -- Innovative Drug Discovery Tool Innovative Drug Discovery Tool --
query molecule
Database Searching
DrugDiscovery
Automated Drug Design
Receptor Mapping
Searchable Molecular Libraries
Jan, 2006 CBIS Conference 22
ThankThank You!You!
[email protected]@umdnj.edu
Visit Us: www.snowdonpharma.com