Conformetrix A new dimension in drug discovery Conformetrix © 2012. All rights reserved. Conformetrix Ltd Background technology and its application to

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

Conformetrix © 2012. All rights reserved.

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)


What we do

Proprietary data analysisStandard NMR

experimentation

Ensemble of ligand

conformations

occupied in solution


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


Example 1: Carazolol

NH

OHO

NH

b2-Adrenergic receptor antagonist.

6 Rotatable bonds.

~106 possible conformations.

Co-crystal available 2007.


Carazolol

Ensemble of all conformations explored in

solution

3 conformations account for 42% of the

population


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


Carazolol

Bioactive conformation (grey) overlayed onto one of the three preferred solution conformations.

Superimposable within the error of the crystal.


Conformetrix structure and co-

crystal.

Computational chemistry and co-

crystal

Conformetrix structure determined within 2 weeks

Carazolol


Example 2: Lisinopril

Angiotensin converting enzyme inhibitor

11 Rotatable bonds

~1011 possible conformations

OOHO

N

NH 2

OOH

NH


Occ

upancy

Conformation index

45% of the occupancy

In 1 of 9 conformations

9 idealised conformations of Lisinopril.

Lisinopril


Ile

Pro

His

Lisinopril

Conformetrix structure vs.

bioactive conformation

Conventional NMR Molecular Modelling Free ligand X-ray


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


Broad applicability

Lisinopril CarazololHyaluronan

TRH

Losartan

AngiotensinII

Tocinoic acid Amikacin


Predictive of bioactive conformation

Lisinopril

Streptomycin

Amikacin

Carazolol

Hyaluronan (HA)

Ivermectin


Potential applications in drug design


Virtual screening

a) Pharmacophore model

b) Single compound

c) Natural ligand


Target 1: TRHR

O

NH

O O O

NH 2N

NH N

NH

Thyrotropin-releasing hormone

TRH - Tripeptide


Thyrotropin-releasing hormone

TRH - Tripeptide

4 modesMulti-modal for dynamic binding or receptor sub-

types?

Target 1: TRHR


12 selected for assay

VS

3.6m

Whole molecule used as pharmacophore model for in silico

screen

Target 1: TRHR


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.


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


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?


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


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


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’


• 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


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


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


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



Repeated with a third scaffold



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



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


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

Documents

Conformetrix A new dimension in drug discovery Conformetrix © 2012. All rights reserved. Conformetrix Ltd Background technology and its application to