Conformetrix Ltd - PowerPoint Presentation

Slide1

Conformetrix LtdBackground technology and its application to drug discovery

Barrie Martin, MedChem

ELRIG Drug Discovery

September 2012 ManchesterSlide2

Key Facts

Spin-out from the University of Manchester, 2008Bionow start-up of the

year, 2008

VC investor – Aquarius Equity Partners

Series A funding to start preclinical research, 2011Bionow emerging technology of the year, 2011First strategic collaboration signed 2012 (AstraZeneca)Slide3

What we do

Proprietary data analysis

Standard NMR experimentation

Ensemble of ligand conformations occupied in solutionSlide4

What we explore

Bi-modal

Population:

50: 50

Uni

-modal

angle: -

77

°

libration

:

25°

Tri-modal

47: 47: 6

The complete conformational space the molecule naturally inhabits…

…which comprises

librations

about mode conformationsSlide5

Example 1: Carazolol

b

2

-Adrenergic receptor antagonist.

6 Rotatable bonds.

~10

6

possible conformations.

Co-crystal available 2007.Slide6

Carazolol

Ensemble of all conformations

explored in solution

3 conformations

account for 42%

of the

populationSlide7

Carazolol

3 conformations

account for 42%

of the

populationSlide8

Carazolol

Bioactive conformation (grey)

overlayed

onto one of the three preferred solution conformations.

Superimposable within the error of the crystal.Slide9

Conformetrix

structure and co-crystal.

Computational chemistry and co-crystal

Conformetrix structure determined within 2 weeks

CarazololSlide10

Example 2: Lisinopril

Angiotensin converting enzyme inhibitor

11 Rotatable bonds

~10

11 possible conformationsSlide11

Occupancy

Conformation index

4

5

% of the occupancyIn 1

of 9

conformations

9 idealised conformations

of

Lisinopril

.

LisinoprilSlide12

Ile

Pro

His

Lisinopril

Conformetrix structure vs. bioactive conformation

Conventional NMR

Molecular Modelling

Free ligand X-raySlide13

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 enrichmentSlide14

Broad applicability

Lisinopril

Carazolol

Hyaluronan

TRH

Losartan

AngiotensinII

Tocinoic acid

AmikacinSlide15

Predictive of bioactive conformation

Lisinopril

Streptomycin

Amikacin

Carazolol

Hyaluronan

(HA)

IvermectinSlide16

Potential applications in drug designSlide17

V

irtual screening

a)

P

harmacophore

model

b

)

S

ingle compound

c) Natural ligandSlide18

Target 1: TRHR

Thyrotropin

-releasing hormone

TRH -

TripeptideSlide19

Thyrotropin

-releasing hormoneTRH -

Tripeptide

4 modes

Multi-modal for dynamic binding or receptor sub-types?

Target 1: TRHRSlide20

12 selected for assay

VS

3.6m

Whole molecule used as pharmacophore model for in

silico

screen

Target 1: TRHRSlide21

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. Slide22

Target 2: GPCR

Type A GPCRNo structural data on target

>340 ligand patents

5

clinical-stage compoundsConformetrix solved structures for 6 published compoundsVirtual screening, de novo design, scaffold hopping and isostere replacement used to identify novel chemistries6 novel active frameworks identified in First Design Sets

Potencies down to 35nMSlide23

Target 2:

isostere replacementMolecule 1

Clinical Candidate

Very potent 5nM

Very flexible: 9 degrees of freedomLipophile

Amide

Lipophile

SCA

Scaffold

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? Slide24

Lipophile

SCA

Scaffold 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

replacementSlide25

1000nM

140nMInactive

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 2Slide26

Conformations demonstrate that the alkyl group acts as a conformational ‘lock’

Provides an alternative explanation for the SAR

1000nM

140nM

Inactive

Target 2: an unexpected ‘lock’Slide27

The two molecules position key interactive groups (amide &

lipophile) in the same relative orientations in solutionMolecule 1

Molecule 2

Conformational Lock

Lipophile

Amide

Target 2: scaffold hopping

140nM

5nM

Overlay of solution conformersSlide28

Conformational Lock

Lipophile

Conformational analysis used to:

identify surprising conformational features;

i

dentify overlapping pharmacophore points;

generate novel scaffolds and IP.

Molecule 1 & 2 hybrid

200nM

Target 2: scaffold hoppingSlide29

Molecule 3;

EC50 = 5nM

70

%

occupancy in one of two conformations

Molecule 4;

EC

50

= 10nM

Scaffold

HBA

Scaffold

HBA

Scaffold

HBA

Scaffold

HBA

51% occupancy in one of two conformations.

Target 3: using consensus overlaysSlide30

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 overlaysSlide31

Repeated with a third scaffold

Target 3: using consensus overlaysSlide32

The

most populated conformation is found in this region in every caseA high

resolution pharmacophore

model has been used to design two

novel series of agonists for this targetPotencies approx. 100nMTarget 3: using consensus overlaysSlide33

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 targetsSlide34

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 ChemistryBarrie Martin

Thorsten Nowak

Technology Development

Andrew Almond

Michael Denison