1 / 47

ADVANCED PARTNERSHIP PLATFORM FOR EARLY DRUG DISCOVERY

ADVANCED PARTNERSHIP PLATFORM FOR EARLY DRUG DISCOVERY. FRAMEWORK OF PRODUCTS AND SERVICES. Fully Integrated Resources For Drug Discovery. HTS Compounds HTS compound collection Pre-plated diversity sets Fragment Libraries Targeted & Focused Libraries. Contract research services

rfred
Télécharger la présentation

ADVANCED PARTNERSHIP PLATFORM FOR EARLY DRUG DISCOVERY

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. ADVANCED PARTNERSHIP PLATFORM FOR EARLY DRUG DISCOVERY

  2. FRAMEWORK OF PRODUCTS AND SERVICES Fully Integrated Resources For Drug Discovery HTS Compounds HTS compound collection Pre-plated diversity sets Fragment Libraries Targeted & Focused Libraries Contract research services Custom Synthesis Computational Chemistry GLP Primary Drug Trials – Key Preclinicals Fine Chemicals in Multigram Scale Advanced Building Blocks IR-Dyes APIs Fine Reagents for Organic Synthesis Scale-up Synthesis (up to 100kg) Process Optimization Off-the-shelf Building Blocks Tangible Building Blocks Cutting-edge Design of Building Blocks Custom Synthesis of Building Blocks and Intermediates

  3. FRAGMENT LIBRARIES The Fragment-based approach is now well established as an efficient tool in modern drug discovery. This method has proven to be more versatile and beneficial over conventional HTS-driven paradigms. Life Chemicals Fragment Collection with variable parameters comprises more than 68,000 screening compounds, containing over 38,000 stock and 30,000 tangible structures. In response to modern FBDD trends Life Chemicals has designed a number of unique Fragment Libraries: General Fragment Library Ultimate Fragment Library Low MW Fragment Library Fragment Library with Experimental Solubility Data Fsp3-enriched Fragment Library 3D Fragment Library Fluorine Fragment Library Fluorine Fragment Cocktails Bromine Fragment Library PPI Fragment Library Covalent Fragments Library Natural Product-like Fragment Library

  4. GENERAL FRAGMENT LIBRARY 38,000 stock available fragments with MW<300 and ClogP<3 Advanced subset of 9,400 Fragments satisfying expanded Ro3 criteria that are perfectly suitable for FBDD purposes Advanced Subset PAINS and compounds with undesired functionalities are removed.

  5. GENERAL FRAGMENT LIBRARY Examples of structures: Advanced Subset:

  6. ULTIMATE FRAGMENT LIBRARY 3,600 fragments with excellent ADME profile for lead generation. Ultimately rigorous selection parameters are applied PAINS and compounds with undesired functionalities are removed.

  7. ULTIMATE FRAGMENT LIBRARY Examples of structures:

  8. LOW MW FRAGMENT LIBRARY The library contains leads with lower molecular weight and higher hydrophilicity. Also included are over 3,000 high quality stock available Fragments selected by means of strict control of molecular weight (100-225 Da) and other essential physico-chemical parameters (cLogP, HDonors, HAcceptors, TPSA, RotB) Finally, the Library is passed through a number of structural filters (MedChem, PAINS). An advanced low molecular weight fragment set of nearly 1,500 compounds was obtained by using even more rigorous physicochemical and structural cut-offs.

  9. LOW MW FRAGMENT LIBRARY Examples of structures:

  10. FRAGMENT LIBRARY WITH EXPERIMENTAL SOLUBILITY DATA We have around 12,500 carefully selected fragments with experimentally measured solubility at 200 mM in DMSO and 1 mM and 5 mM in pH 7.5 phosphate buffer solution (turbidimetry method). Average MW = 243 Da, average cLogP = 1.3 Guaranteed solubility of all compounds in DMSO at very high concentration (200 mM) More than 75 % of fragments are also soluble in PBS buffer at 1mM and 60 % are soluble at 5mM

  11. FRAGMENT LIBRARY WITH EXPERIMENTAL SOLUBILITY DATA Examples of structures:

  12. FSP3-ENRICHED FRAGMENT LIBRARY Fsp3-enriched Fragment Library comprises more than 11,500 compounds with inherent high selectivity towards pharmacological targets. Physicochemical parameters of advanced Fsp3-enriched fragments (about 3,200 compounds) are summarized in the table below: Fsp3 distribution

  13. FSP3-ENRICHED FRAGMENT LIBRARY Examples of structures:

  14. 3D FRAGMENT LIBRARY 1,500 carefully designed drug-like 3D fragments Special selection by physicochemical properties and principal moments of inertia (PMI) to improve 3D-shape functionality and diversity of the molecules Diversity filtering using linear fingerprints (Tanimoto coefficient 88%) Life Chemical 3D fragments library covers various shapes: rod-like, disk-like and spherical with sufficient diversity. PAINS and compounds with undesired functionalities are removed.

  15. 3D FRAGMENT LIBRARY Examples of structures:

  16. FLUORINE FRAGMENT LIBRARY 19F NMR-based fragment screening can be used as a very efficient tool for rapidand sensitive detection of fragment hits. 3,300 fluorine-containing fragments including Advanced Subset of 2,000 compounds are available in stock. Fluorine Fragment Library – Advanced subset Metal containing and reactive compounds, undesired chemotypes, salts and PAINS are discarded. “Fragment space” coverage of Life Chemicals Fluorinated fragments (in black) is similar to the coverage of all commercially available fluorinated fragments (in red).

  17. FLUORINE FRAGMENT LIBRARY Examples of structures:

  18. FLUORINE FRAGMENT COCKTAILS The efficiency of fragment screening can be increased substantially by pooling compounds in pools of up to 15 fragments. Identification of the bound fragments by NMR, X-ray or ligand-observed LC/MS experiments then becomes a case of determining the best fragment-fits. Life Chemicals prepared an exclusive set of fluorine-containing fragment cocktails based on 1,000 fragments selected from Fluorine-based Fragment Library. Each fragment pool contains 10 fragments. Fragments are carefully selected to ensure most different 19Fchemical shifts within each pool. 19F NMR spectra are available for every fragment

  19. FLUORINE FRAGMENT COCKTAILS Carefullycollected 100+ cocktailscomprisedrug-likefluorinefragmentssatisfyingthe followingparameters: Mostlyonly 1 peakin19F NMR spectrum Purity 95%+ DMSO solubleat 200 mM Structure Filters applied: no reactive functional groups Lilly MedChem rules PAINS Ring count 1 – 3 PhysChem Parameters: 130 < MW < 300 -1.7 < ClogP < 3.0 H-bond Donors ≤ 3 H-bond Acceptors ≤ 4 TPSA ≤ 110 Å2

  20. FLUORINE FRAGMENT COCKTAILS Example of 19F NMR spectrum of the fragment cocktail with signals associated with each compound

  21. BROMINE FRAGMENT LIBRARY Bromine atom can be located uniquely due to anomalous scattering that enables recognizing the structure of fragment-target complex 1,300 bromine-containing fragment to be used in crystallographic FBDD Compounds with MW ≤ 350 and ClogP ≤ 3.5 are selected. All the fragments contain only one Br atom. Reactive compounds, undesired chemotypes, PAINS are removed. An advanced subset of more than 800 compounds is also available selected by the following criteria: ClogP < 3.5 Molecular weight < 350 Da H-bond acceptors = 0−4 H-bond donors = 0−3 Rotatable bonds <= 4 Number of rings = 1−3

  22. BROMINE FRAGMENT LIBRARY Examples of structures:

  23. PPI FRAGMENT LIBRARY About 2,500 in-stock fragments potentially capable of PPI inhibition Selected using advanced set of descriptors and specially designed ranking mechanism1 Hydrophobic and more spatial structures (sp3-enriched) to enhance selectivity2 Excellent coverage of 3D shape space with good diversity3 PMI plot showing distribution of Life Chemicals PPI fragments in 3D shape space • 1Reynès C., Host H., Camproux A.C. et al. PLoSComput. Biol., 2010, 6(3):e1000695 • 2 Fry D.C. Protein-protein interactions as targets for small molecule drug discovery. Biopolymers,2006, 84, 535–52. • 3Carr R.A.E. et al. Fragment-based lead discovery: leads by design. Drug Discov. Today,2005, 10, 987–92.

  24. PPI FRAGMENT LIBRARY Examples of structures:

  25. COVALENT FRAGMENT LIBRARY • 1,300carefully selected Ro3 compliant covalent binders • Compounds with specific structural fragments (functional groups)that are known to form covalent bonds with amino acid residues in binding sites of target proteins: Lys, Cys, Ser, Asp, Glu, His and Tyr: • Acetals • Acrylamides • Acrylonitriles • -Dicarbonyl compounds • Aliphatic thiols • Aromatic thiols • Epoxides • Ketals • Maleimides and related compounds • Other Michael acceptors • Quinones • Sulfonate esters • Sulfonyl halides • Terminal acetylenes • Thioureas and thiones • Vinyl sulfones and vinyl sulfonamides • Other types Molecules with highly reactive electrophilic and nucleophilic groups, compounds with non drug-like cores were removed using selected unwanted cores filters and selected PAINS filters.

  26. COVALENT FRAGMENT LIBRARY Examples of structures:

  27. NATURAL PRODUCT-LIKE FRAGMENT LIBRARY A new fragment library recently added to Life Chemicals collection Designed using Scaffold Tree analysis1 of Universal Natural Product Database2 (comprising more than 220,000 Natural Products) as the starting point More than 3,200 fragments obtained from NP-derived or NP-like scaffolds • 1Schuffenhauer, A.; Ertl, P.; Roggo, S.; Wetzel, S.; Koch, M. A.; Waldmann H. J ChemInf Model. 2007, 47, 47–58. • 2Gu, J.; Gui, Y.; Chen, L.; Yuan, G.; Lu, H.-Z.; Xu, X. PLoS ONE, 2013, 8, e62839.

  28. INNOVATIVE DESIGN OFCOMPOUND LIBRARY FOR FBDD • Specially designed and synthesized for FBDD • High novelty of chemical structures Diversity analysis VS eMoleculesand most common vendors databases • Diversification of the Library includes: Linear fingerprint, pharmacophore and 3D analysis • High quality of molecules: rigorous physicochemical parameters, PAINS and in-house developed structure filters • Rapid SAR generation potential Quick selection and synthesis of molecules for follow-up testing analogues

  29. DEDICATED DESIGN OF COMPOUND LIBRARY FOR FBDD 1st Step. Virtual coupling 1,139 Building Blocks carefully selected novel Fsp3-enriched molecules + 1,246 Decorating reagents pharmacologically privileged and selected by Phys-Chem parameters structures 463,000 compounds

  30. DEDICATED DESIGN OF COMPOUND LIBRARY FOR FBDD 2nd Step. Phys-Chem parameters “Rule of three”-like restrictions: • 150 < MW < 300 • –2 < ClogP < 3 • HDon ≤ 3 • HAcc ≤ 4 • RotB ≤ 3 Other requirements • TPSA ≤ 70 Å2 • clogSw > –3 • Heavy atoms (HAC) ≤ 20 Structural filtering parameters • PAINS & in-house developed filters for undesired and reactive functionalities • At least one ring in structure; no more than two fused aromatic rings • No more than one S, Cl, Br; no more than three F • Min one additional atom N, O apart from the main functional group • No N-arylsulfonamides, no tetrazoles, no more than 5% of compounds with isolated benzene ring

  31. DEDICATED DESIGN OF COMPOUND LIBRARY FOR FBDD 3rd Step. Novelty verification 98 % Tanimoto dissimilarity to eMolecules database 98 % Tanimoto dissimilarity to Major Competitors Fragment Databases 90 % Tanimoto dissimilarity to Life Chemicals Stock Collection 62,000 compounds

  32. DEDICATED DESIGN OF COMPOUND LIBRARY FOR FBDD 4th Step. Complex diversity approach Tanimotodissimilary selection 87% 3D Shape analysis Pharmacophore diversity analysis Complexity optimization 21,200 compounds

  33. DEDICATED DESIGN OF COMPOUND LIBRARY FOR FBDD 5th Step. Final set formation Chemotype control Possibility of evolution (ideally 2 points) Synthetic considerations Scaffold population analysis Advanced Set of Tangible Fragments 5,202 compounds

  34. DEDICATED DESIGN OF COMPOUND LIBRARY FOR FBDD Physicochemical  properties analysis: mean Fsp3= 0.58 Maybridge Ro3 set: mean Fsp3 = 0.30 mean HAC = 16.5

  35. DEDICATED DESIGN OF COMPOUND LIBRARY FOR FBDD Physicochemical properties analysis: mean MW = 232 mean HAcc=2.9 mean TPSA =39 Å2 mean HDon= 0.3

  36. DEDICATED DESIGN OF COMPOUND LIBRARY FOR FBDD Physicochemical properties analysis: mean LogP = 1.1 mean logPSw = –1.5 mean RingCount = 2.5 mean RotB = 2.0

  37. DEDICATED DESIGN OF COMPOUND LIBRARY FOR FBDD Examples of building blocks:

  38. DEDICATED DESIGN OF COMPOUND LIBRARY FOR FBDD Examples of reagents:

  39. DEDICATED DESIGN OF COMPOUND LIBRARY FOR FBDD Examples of fragments:

  40. DEDICATED DESIGN OF COMPOUND LIBRARY FOR FBDD More than 1000 compounds with stock weight of over 100 mg Examples of already synthesized fragments:

  41. DEDICATED DESIGN OF COMPOUND LIBRARY FOR FBDD References Boyd S. M., de Kloe G. E. Fragment library design: efficiently hunting drugs in chemical space. Drug Discovery Today: Technologies 2010, 7, 173–180. Collins I., Jones A. M. Diversity-oriented synthetic strategies applied to cancer chemical biology and drug discovery. Molecules, 2014, 19, 17221–17255. Langdon S. R., Brown N., Blagg J. Scaffold diversity of exemplified medicinal chemistry space. J. Chem. Inf. Model. 2011, 51, 2174–2185. Joseph-McCarthy D., Campbell A. J., Kern G., Moustakas D. Fragment-based lead discovery and design. J. Chem. Inf. Model., 2014, 54, 693−704. Koutsoukas A., Paricharak S., Galloway W. R. J. D. et. al. How diverse are diversity assessment methods? A comparative analysis and benchmarking of molecular descriptor space. J. Chem. Inf. Model. 2014, 54, 230−242. Morley A. D., Pugliese A., Birchall K. et al. Fragment-based hit identification: thinking in 3D. Drug Discovery Today, 2013, 18, 23–24, 1221–1227. Boyd S. M., Turnbull A. P. , Walse B. Fragment library design considerations. Comput. Mol. Sci.,2012, 2, 868–885. Schulz M. N., Landström J., Bright K., Hubbard R. E. Design of a fragment library that maximally represents available chemical space. J. Comput. Aided Mol. Des., 2011, 25, 611–620.

  42. LIFE CHEMICALS GEOGRAPHY Total number of employees: Over 110, including 61 chemists (1 Prof, 11 PhDs, 35 MSc, 14 BSc) Production space: 2,500 m2

  43. SCREENING COMPOUNDS – GENERAL INFO Our Products 460,000 compounds in stock 2,900 original scaffolds Fsp³ enriched Library: 38,000 compounds 900,000 tangible compounds Pre-plated diversity sets (non-overlapping): 5,000, 10,000, 15,000 and 20,000compounds, with all these sets enabling to obtain a “blanket” collection of 50,000 uniquestructures Quality and Handling standards: Over 90 % purity, confirmed by LCMS and/or 400MHz NMR Prompt delivery in any container as powder or DMSO solution Bar-coding and labeling according to customers’ requirements

  44. ORDER HANDLING Life Chemicals guarantees high quality service and flexibility Inquiry: quotation within 0-3 business days Order: the process is launched immediately after the order Synthesis (for non-stock compounds): normally 2-6 weeks, progress reports are provided upon request Quality control: high quality standards (purity of 90 – 95 % confirmed with NMR and/or LCMS) Delivery: 3-7 days by FedEx to any destination (customer’s FedEx account can be used) Payment: by cheque, credit card or wire transfer to the account in Germany or in Canada, payment terms are NET 30 days. For small stock orders you can go directly to our shop at https://shop.lifechemicals.com/ Inquiry Order Synthesis QC Delivery Payment

  45. QUALITY ASSURANCE AND ORDER PROCESSING Structure of compounds is validated by analytical data,400 MHz NMR and/or LCMS analysis. Analytical data is readily available upon the customer’s request ISIS .db or .sdf files are enclosed with every shipment Sample weights: 1 mg - 0.5 g with 0.1 mg weighing precision, mg, micromole amounts Compounds forms:- dry powders- frozen DMSO solutions Formatting:- Standard 4mL, 15mm*45mm, amber borosilicate glass vials withrubber-lined plastic screw caps- 96 well PP-masterblocks, Greiner bio-one ref: 780215, U-bottom 1.0ml- 96 well plates, Matrix cat.# 4247, racked round-bottom tubes, 1,4 ml Each plate/box of vials is barcoded and labeled to meet the customer’s requirements

  46. OUR FIELDS OF EXPERTISE Strong position in organic synthesis and medicinal chemistry Successful experience in custom synthesis projects of high complexity, including multistep procedures Co-design with customers Synthesis of reference compounds Synthesis of impurities Broadest range of compounds and chemical transformations Scale-up from grams to kilograms Recognized scientific portfolio Cutting-edge techniques and approaches Primary drug trial services Qualified and experienced staff Customer-tailored terms and conditions IP protection Timely and efficient data transfer

  47. WHY LIFE CHEMICALS? The Company has strong and recognized position in organic synthesis and medicinal chemistry. Novel chemistry and highest quality Our product catalogue includes over 460,000 screening compounds and 12,000 in-house synthesized building blocks Hit resupply Experienced project management Experience in creating of discovery products (targeted libraries, FBDD) Developed platform (analytic labs, logistics, etc.) Access to literature (Reaxys, SciFinder, DiscoveryGate) Chemical Informatics support Our chemists can tackle tasks of highest complexity We work as a fully integrated platform to offer best products and services.

More Related