C4XD.L Conformetrics and its applica6on in drug discovery
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1 C4XD.L Conformetrics and its applica6on in drug discovery Dr Thorsten owak; 1 st Anglo-ordic-MedChem Conference 11 th 14 th June
2 CTET Conformetrics, what it is and how its used in drug discovery at C4X IntroducDon Experimentally led conformadonal analysis C4X Discovery Technology in a nutshell ApplicaDon of the technology highlights from projects... ü Keap1/rf2 PPIs ü IL17 PPIs 2
3 CFRMATIAL AALYSIS DRIVE BY EXPERIMET Experimentally determined conforma6onal preferences L-histidine H H 3 FAJMIP 3
4 X-RAY CRYSTALLGRAPHY Mul6ple forms of a single molecule in the CSD can reflect conforma6onal diversity and preferences L-histidine χ1 χ2 H H 3 χ2 χ1 CSD crystal conformations 75 forms (some organic salts; Asp, AMP, camp) (divalent metal ions may skew populations) 4
5 HISTIDIE SLUTI ESEMBLE FRM MR DATA Free solu6on 4D-structure L-histidine H H 3 χ2 χ ±0.05 χ1 libration 14± ± ± ±6 0.27±0.05 χ2 libration 18±8 90±6 0.22± ±6 0.49±0.08 Ensemble-4D 5
6 HISTIDIE SLUTI ESEMBLE FRM MR DATA Free solu6on 4D-structure 0.25 χ1 χ ±0.05 libration 14±7 libration 18± ± ±6 0.27± ±6 0.22± χ ± ±6 0.49±0.08 Ensemble-4D 6
7 SLID STATE VS SLUTI CFRMATIS χ1 χ2 Free solution 4D-structure ± ± ±6 0.27± ±6 0.22±0.05 H H 3 χ2 χ1 libration 14± ±0.09 libration 18±8 114±6 0.49±0.08 CSD crystal conformations 75 forms 7
8 PRPRIETARY, PATETED-PRTECTED METHDLGY MR data Proprietary sozware suite 4D-structure Quan6fica6on of free ligand conforma6onal preferences by MR and their rela6onship to the bioac6ve conforma6on Blundell CD, Packer MJ and Almond A, Bioorganic & Medicinal Chemistry, 21 (17), (2013) 8
9 APPLICABLE T ALL DRUG AD TARGET CLASSES TARGET AGSTIC 9
10 SLUTI 4D-STRUCTURES PREDICT TARGET-BUD (BIACTIVE) CFRMATIS BrefeldinA Simpanorm Devomycin CydecDn Lisinopril Gleevec Hyaluronic acid 10
11 C4XD.L The power of combining Conformetrics and Docking strategies for SBDD Keap1/rf-2 PPIs
![affinity (~1µM [LE 0.25])?](/docs-images/86/93510634/images/12-4.jpg "H SRS- 5 2 idealised conformers Hu, L.; et al. Bioorg.")
12 EXPERIMETALLY CHARACTERISED BUD VERSUS UBUD FRMS Rigidity How much and where? Is excessive rigidity the reason for poor affinity? Are non-optimal interactions the reasons for weak affinity (~1µM [LE 0.25])? H SRS- 5 2 idealised conformers Hu, L.; et al. Bioorg. Med. Chem. Le^. (2013), 23, Bound vs Solution 12
13 DCKIG STUDIES (GLIDE) FLEXIBLE LIGAD APPRACH Flexible ligand docking with post docking minimiza6on input crystal structure conforma6on (4L7B) (a) Rank: 1, 2, 7 (b) Rank: 3, 5, 10 Jan-Christoph Westermann 13
14 DCKIG STUDIES (GLIDE) RIGID LIGAD APPRACH Rigid body docking of C4X conforma6onal ensemble (250 conformers) with post-docking minimiza6on Minor Conformer 7% Major Conformer 90% (a) 4L7B (b) Rank: 1 20 (Approx. 3% minor E-Amide Conformer) Jan-Christoph Westermann 14
15 TARGETED, CFRMATIALLY CTRLLED LIGAD GRWTH Prove of hypothesis that ligand extension leads to potency increase Target ligand growth using conformadonal database informadon to design linkers C4XD internal knowledge CSD knowledge base PDB knowledge base 15
16 C4XD.L The power of conforma6onal restric6on IL-17 - PPIs
17 IL-17 WHAT IS KW? Conforma6onal diversity as an opportunity SRS-5 Keap1/rf-2 Pfizer IL17 inhibitor H H H H F 2 idealised conformers extremely rigid Liu, S., et al. Scientific Reports, (2016), 6, idealised conformers extremely flexible 17
18 IL-17 KW LIGADS AD THE BIDIG MDES PDB 5HI3; DI: /srep
19 IL-17 CFRMATIAL DIVERSITY AS A PPRTUITY I DRUG DISCVERY Ra6onal reduc6on of conforma6onal diversity as a design opportunity 480 idealised conformers 19
20 IMPACT F CFRMATIAL DESIG IL-17 PTECY Ensemble References Pfizer open chain LE HI Project Phase H2L 20
21 SUMMARY Conforma6onal design is an integral strategy in medicinal chemistry Experimentally determined conformadonal data are rich sources for design strategies complemendng tradidonal potency and property focused approaches. Experimentally determined conformadonal data expand the udlity of structural biology informadon. Experimentally determined conformadonal data offers addidonal opportunides for computadonal chemistry. 21
22 ACKWLEDGEMETS C4X Colleagues Collaborators/Providers of tools Wojtek Augustyniak Jan-Christoph Westermann Sadia Mohammed Jon Bryne MarDn Watson Charles Blundell ick Ray Barrie MarDn Emma Blaney Proteros Biostructures GmbH Schrodinger Inc. The Cambridge Crystallographic Datacentre 22
23 C4XD.L Thank you! 23
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Fragment based lead discovery - introduction György M. Keserű H2020 FRAGET etwork Hungarian Academy of Sciences www.fragnet.eu Hit discovery from screening Druglike library Fragment library Large molecules
Supplementary Material
upplementary Material Molecular docking and ligand specificity in fragmentbased inhibitor discovery Chen & hoichet 26 27 (a) 2 1 2 3 4 5 6 7 8 9 10 11 12 15 16 13 14 17 18 19 (b) (c) igure 1 Inhibitors
ing equilibrium i Dynamics? simulations on AchE and Implications for Edwin Kamau Protein Science (2008). 17: /29/08
Induced-fit d or Pre-existin ing equilibrium i Dynamics? Lessons from Protein Crystallography yand MD simulations on AchE and Implications for Structure-based Drug De esign Xu Y. et al. Protein Science