ConformetrixA new dimension in drug discoveryConformetrix © 2012. All rights reserved.
Conformetrix LtdBackground technology and
its application to drug discovery
Barrie Martin, MedChem
ELRIG Drug Discovery September 2012 Manchester
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Key Facts
Spin-out from the University of Manchester,
2008
Bionow start-up of the year, 2008
VC investor – Aquarius Equity Partners
Series A funding to start preclinical research,
2011
Bionow emerging technology of the year, 2011
First strategic collaboration signed 2012
(AstraZeneca)
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What we do
Proprietary data analysisStandard NMR
experimentation
Ensemble of ligand
conformations
occupied in solution
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What we explore
Bi-modalPopulation: 50: 50
Uni-modalangle: -77 °libration: 25°
Tri-modal47: 47: 6
The complete conformational space the molecule naturally
inhabits…
…which comprises librations about mode conformations
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Example 1: Carazolol
NH
OHO
NH
b2-Adrenergic receptor antagonist.
6 Rotatable bonds.
~106 possible conformations.
Co-crystal available 2007.
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Carazolol
Ensemble of all conformations explored in
solution
3 conformations account for 42% of the
population
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Carazolol
3 conform
ations
24 conform
ations
54 conform
ations
0%
10%
20%
30%
40%
50%
60%
% occupancy of conformations in solution
Occupancy
3 conformations account for 42% of the
population
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Carazolol
Bioactive conformation (grey) overlayed onto one of the three preferred solution conformations.
Superimposable within the error of the crystal.
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Conformetrix structure and co-
crystal.
Computational chemistry and co-
crystal
Conformetrix structure determined within 2 weeks
Carazolol
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Example 2: Lisinopril
Angiotensin converting enzyme inhibitor
11 Rotatable bonds
~1011 possible conformations
OOHO
N
NH 2
OOH
NH
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Occ
upancy
Conformation index
45% of the occupancy
In 1 of 9 conformations
9 idealised conformations of Lisinopril.
Lisinopril
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Ile
Pro
His
Lisinopril
Conformetrix structure vs.
bioactive conformation
Conventional NMR Molecular Modelling Free ligand X-ray
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Example 3: Angiotensin(1-7)
Peptide/ligand overlay
on key pharmacophore
points
Solution structures of endogenous ligands can act as the
template for drug design and library enrichment
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Broad applicability
Lisinopril CarazololHyaluronan
TRH
Losartan
AngiotensinII
Tocinoic acid Amikacin
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Predictive of bioactive conformation
Lisinopril
Streptomycin
Amikacin
Carazolol
Hyaluronan (HA)
Ivermectin
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Potential applications in drug design
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Virtual screening
a) Pharmacophore model
b) Single compound
c) Natural ligand
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Target 1: TRHR
O
NH
O O O
NH 2N
NH N
NH
Thyrotropin-releasing hormone
TRH - Tripeptide
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Thyrotropin-releasing hormone
TRH - Tripeptide
4 modesMulti-modal for dynamic binding or receptor sub-
types?
Target 1: TRHR
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12 selected for assay
VS
3.6m
Whole molecule used as pharmacophore model for in silico
screen
Target 1: TRHR
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C4X_1_03
First Non-Peptidic TRHR agonist
Target 1: TRHR
Overlay of structures highlights similar range of motions and next steps for Med Chem.
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Target 2: GPCR
Type A GPCR
No structural data on target
>340 ligand patents
5 clinical-stage compounds
Conformetrix solved structures for 6 published compounds
Virtual screening, de novo design, scaffold hopping and
isostere replacement used to identify novel chemistries
6 novel active frameworks identified in First Design Sets
Potencies down to 35nM
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Target 2: isostere replacement
• Molecule 1
• Clinical Candidate
• Very potent 5nM
• Very flexible: 9 degrees of freedom
Lipophile Amide LipophileSCAScaffold
• One major shape in solution
• 80% occupancy
• Several conformational features
identified that confer the 3D shape
Conformetrix
Can a Conformetrix structure be used for design in the same way as co-crystal structure?
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LipophileSCAScaffold Redesign
Opportunity to Cyclise
Conformational Lock
Lipophile Amide
Scaffold Redesign 35nM
Cyclisation 100nM
• Indicates that we have been able to discover the bioactive conformation
• Analogous to drug design with X-ray co-crystallography
• But, this is a GPCR target with no structural information available
Two novel series of potent compounds identified in first design set
Target 2: isostere replacement
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1000nM 140nM Inactive
A
O
NR2
R1
NH
Ar
A
O
NR2
R1
NH
ArR2O
N
R
NH
Ar
140nM published candidate compound generated by introduction of a small chiral group
The improved potency of molecule 2 over the parent compound and the inactive enantiomer was explained by enhanced lipophilic interaction
Target 2: an unexpected ‘lock’
Molecule 2
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Conformations demonstrate that the alkyl group acts as a conformational ‘lock’
Provides an alternative explanation for the SAR
1000nM 140nM Inactive
A
O
NR2
R1
NH
Ar
A
O
NR2
R1
NH
ArR2O
N
R
NH
Ar
Target 2: an unexpected ‘lock’
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• The two molecules position key interactive groups (amide & lipophile) in
the same relative orientations in solution
Molecule 1 Molecule 2
Conformational Lock
Lipophile Amide
A
O
NR2
R1
NH
Ar
Target 2: scaffold hopping
140nM5nM
Overlay of solution conformers
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O
NR2
R1Conformational Lock
Lipophile
• Conformational analysis used to:
• identify surprising conformational features;
• identify overlapping pharmacophore points;
• generate novel scaffolds and IP.
Molecule 1 & 2 hybrid
200nM
Target 2: scaffold hopping
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Molecule 3; EC50 = 5nM
70% occupancy in one of two conformations
Molecule 4; EC50 = 10nM
ScaffoldHBA Scaffold
HBAScaffold
HBA
ScaffoldHBA
51% occupancy in one of two conformations.
Target 3: using consensus overlays
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Surprisingly, Molecule 3 is more flexible than Molecule 4 in solution
The two ligands have a consensus area in their ensembles
This area is equivalent to one of the most occupied conformations of both molecules
Target 3: using consensus overlays
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Repeated with a third scaffold
Target 3: using consensus overlays
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The most populated conformation is found in this region in every case
A high resolution pharmacophore model has been used to design two novel series of agonists for this target
Potencies approx. 100nM
Target 3: using consensus overlays
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Technology summary
Conformetrix technology has shown that flexible molecules exist in
solution in a limited number of conformations.
Of these idealised conformations, one always closely resembles the
bioactive conformation.
Conformational analysis can be used to identify common
pharmacophore features, conformational ‘locks’ and unfavourable
conformations to direct de novo design, scaffold hopping and virtual
screening.
Early evidence from pre-clinical projects has shown that
Conformetrix’s approach can be used to identify potent, novel
chemistries against valuable targets
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Conformetrix
Board
Clive Dix
(Chairman)
Sam Williams (CEO)
Charles Blundell
(CSO)
Andrew Almond
(CTO)
Harry Finch
Duncan Peyton
Alex Stevenson
NMR Spectroscopy
Charles Blundell
Martin Watson
Wojtek Augustyniak
Jonathon Byrne
Jan-Christoph
Westermann
Medicinal Chemistry
Barrie Martin
Thorsten Nowak
Technology
Development
Andrew Almond
Michael Denison