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Conformetrix Ltd Background technology and its application to drug discovery

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  1. Conformetrix Ltd Background technology and its application to drug discovery Barrie Martin, MedChem ELRIG Drug Discovery September 2012 Manchester

  2. 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)

  3. What we do Ensemble of ligand conformations occupied in solution Standard NMR experimentation Proprietary data analysis

  4. What we explore • The complete conformational space the molecule naturally inhabits… Bi-modal Population:50: 50 Uni-modal angle: -77 ° libration: 25° Tri-modal 47: 47: 6 • …which comprises librations about mode conformations

  5. Example 1: Carazolol • b2-Adrenergic receptor antagonist. • 6 Rotatable bonds. • ~106 possible conformations. • Co-crystal available 2007.

  6. Carazolol Ensemble of all conformations explored in solution 3 conformations account for 42% of the population

  7. Carazolol 3 conformations account for 42% of the population

  8. Carazolol • Bioactive conformation (grey) overlayed onto one of the three preferred solution conformations. • Superimposable within the error of the crystal.

  9. Carazolol Computational chemistry and co-crystal Conformetrix structure and co-crystal. Conformetrix structure determined within 2 weeks

  10. Example 2: Lisinopril • Angiotensin converting enzyme inhibitor • 11 Rotatable bonds • ~1011 possible conformations

  11. Lisinopril 45% of the occupancy In 1 of 9conformations Occupancy 9 idealised conformations of Lisinopril. Conformation index

  12. Lisinopril Conformetrix structure vs. bioactive conformation Ile Pro His Conventional NMR Molecular Modelling Free ligand X-ray

  13. 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

  14. TRH AngiotensinII Amikacin Carazolol Losartan Hyaluronan Lisinopril Tocinoic acid Broad applicability

  15. Predictive of bioactive conformation Amikacin Ivermectin Lisinopril Streptomycin Hyaluronan (HA) Carazolol

  16. Potential applications in drug design

  17. Virtual screening a) Pharmacophore model b) Single compound c) Natural ligand

  18. Target 1: TRHR Thyrotropin-releasing hormone TRH - Tripeptide

  19. Target 1: TRHR Thyrotropin-releasing hormone 4 modes Multi-modal for dynamic binding or receptor sub-types? TRH - Tripeptide

  20. Target 1: TRHR VS Whole molecule used as pharmacophore model for in silico screen 3.6m 12 selected for assay

  21. Target 1: TRHR First Non-Peptidic TRHR agonist Overlay of structures highlights similar range of motions and next steps for Med Chem. C4X_1_03

  22. 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

  23. Target 2: isostere replacement Can a Conformetrix structure be used for design in the same way as co-crystal structure? SCA Lipophile Scaffold Lipophile Amide • Molecule 1 • Clinical Candidate • Very potent 5nM • Very flexible: 9 degrees of freedom • One major shape in solution • 80% occupancy • Several conformational features identified that confer the 3D shape Conformetrix

  24. Target 2: isostere replacement Conformational Lock SCA Lipophile Scaffold Redesign Lipophile Amide Opportunity to Cyclise Scaffold Redesign 35nM Cyclisation 100nM Two novel series of potent compounds identified in first design set • 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

  25. Target 2: an unexpected ‘lock’ 1000nM 140nM Inactive Molecule 2 • 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

  26. Target 2: an unexpected ‘lock’ 1000nM 140nM Inactive • Conformations demonstrate that the alkyl group acts as a conformational ‘lock’ • Provides an alternative explanation for the SAR

  27. Target 2: scaffold hopping Conformational Lock Lipophile Amide Molecule 2 Molecule 1 140nM 5nM Overlay of solution conformers • The two molecules position key interactive groups (amide & lipophile) in the same relative orientations in solution

  28. Target 2: scaffold hopping Conformational Lock Lipophile Molecule 1 & 2 hybrid 200nM • Conformational analysis used to: • identify surprising conformational features; • identify overlapping pharmacophore points; • generate novel scaffolds and IP.

  29. Target 3: using consensus overlays 70% occupancy in one of two conformations HBA Scaffold Scaffold HBA Molecule 3; EC50 = 5nM 51% occupancy in one of two conformations. HBA Scaffold HBA Scaffold Molecule 4; EC50 = 10nM

  30. 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

  31. Target 3: using consensus overlays Repeated with a third scaffold

  32. Target 3: using consensus overlays 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

  33. 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

  34. 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 • WojtekAugustyniak • Jonathon Byrne • Jan-ChristophWestermann • Technology Development • Andrew Almond • Michael Denison • Medicinal Chemistry • Barrie Martin • Thorsten Nowak