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    Fragments

    • Our fragment libraries are based on experimentally validated design principles
    • Technology Enabled Libraries allow access to unique fragments
    • Pharmacophore Optimized Libraries maximize the hit rate in fragment screens
    • Covalent Minifrag Library improves hit identification by small fragments

    Fragment screening has become an increasingly popular¹ way to identify viable chemical starting points due to a number of potential advantages over the screening compounds with larger complexity.

    Although, in contrast to larger compounds, a fragment has typically fewer interactions with the target protein and thus lower affinity overall. On the other hand, thermodynamic and probabilistic models of small molecule – macromolecule binding suggest that these fragment-protein interactions are individually of greater energetic reward. Additionally, screening can more effectively sample the chemical space with smaller, less complex compounds, which improves the odds of identifying binders with high ligand efficiency.

    Fragments may thus provide medicinal chemists with a higher number of promising candidates and, owing to their smaller size, a greater flexibility in the optimization process and larger freedom-to-operate space.

    However, apart from these advantages, fragment-based approaches have a number of limitations. It can be challenging to detect weak-affinity fragment hits and effectively distinguish them from false positives. Furthermore, structural information describing the atomic interactions between the fragment hit and its protein target is typically needed for successful fragment optimization, but such information might be difficult to obtain in some certain cases.

    Druglike library

    • Large molecules (MW>300)

    • Large library (10⁶ compounds)

    • Biochemical testing

    • Less diverse hits

    • High affinity (1-10 µm)

    Fragment library

    • Small molecules (MW<300)

    • Small library (10³ fragments)

    • Biophysical testing

    • Diverse hits

    • Low affinity (<100 µM)

    Design Principles

    Success depends on the quality of the fragment library, and this is where ComInnex has a chance to serve its clients. The take-off point is to cover the part of the fragment’s chemical space which is not covered by present vendors yet and providing coverage for the relevant subspace.
    A study conducted by Chris Swain² compared the physchem properties (e.g size, shape, HBA, HBD and lipophilicity) of commercial fragments and that of actual fragment hits. They found that fragment hits have lower molecular weight, they contain a greater proportion of ionisable groups and aromatic rings than the commercial fragments. More recently D.E. Shaw and co-workers analysed a large number of fragment protein complexes.³ In fact, these findings challenge the generally accepted criteria used for compiling fragment libraries.⁴

    The fragment criteria used to design ComInnex’s Fragment Sets reflect these changes of design principles (table below). PAINS and in-house developed filtering parameters, such as toxicophore and undesired functionalities, were applied to make up the set of compounds shown here.

    ParameterRange
    MW≤ 250
    logP0-3
    HAC≥ 8
    HBA1-4
    HBD1-2
    TPSA≤ 85 Ų
    Rotatable bonds≤ 5
    Rings count1-3
    logS≥ -3.5

     

    Libraries

    In response to this evident trend in drug discovery ComInnex has designed its Fragment Libraries containing nearly 4000 compounds. Following the most promising current tendencies in fragment based approach to drug discovery, ComInnex has prepared a selection of its unique subsets given below. Exluding the Pharmacophore Optimised Fragment Libraries, cherry-picking available, delivery in custom format including dry powders or DMSO solution in vials, microtubes or plates.

    1. Technology Enabled Fragment Library I (1146 compounds)
    2. Technology Enabled Fragment Library II (387 compounds)
    3. Pharmacophore Optimised Fragment Library I (96 compounds)
    4. Pharmacophore Optimised Fragment Library II (96 compounds)
    5. High Fsp³ Fragment Library (209 compounds)
    6. Covalent Minifrag Library (82 compounds)
    7. General Fragment Library (2471 compounds)

    Fragment Hopping

    One of the key advantages of these libraries is that ComInnex provides fast and effective fragment hopping from fragment hits identified from these libraries. Owing to synthesis routes developed we are able to deliver a set of follow-up compounds from the surroundings of the hits in short time that would facilitate hit confirmation, early optimization and SAR studies.

    1. Technology Enabled Fragment Library I

    These compounds are based on the technology enabled chemistry available at ComInnex, that fulfil the above mentioned physchem criteria: MW ≤ 250; 0≤LogP≤3; 1≤HBA≤4; 1≤HBD≤2 and that have unique pharmacophore. We use a range of technologies like flow and photochemistry to develop methods for unique compounds. Synthesis of the core structure followed by parallel chemistry, led to a number of available analogues. In case a customer has a hit among the set of fragments, analogues of the hit and a virtual library can also be offered. Compounds can be synthesized within only 3 weeks.

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    2. Technology Enabled Fragment Library II

    The Technology Enabled Fragment Library II contains 387 compounds that fulfil the physchem criteria: MW ≤ 250; -1≤LogP≤3; 1≤HBA≤4; 1≤HBD≤2. These compounds are on stock and ready to deliver within 10 days.

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    3. Pharmacophore Optimised Fragment Library I

    To improve the hit list further we have analysed of the pharmacophore space of validated fragment hits. We have explored of the binding pharmacophores in protein-fragment complexes available in PDB and we have identified 154 pharmacophore arrangements that occurring in at least 5 different proteins. In order to assess the molecular complexity and diversity of our set, pharmacophore graph triangle fingerprints (GpiDAPH3)³ were calculated. Having the fingerprints, a hierarchic clustering method has been elaborated, which groups the compounds based on the pharmacophore triangles. In this way we can choose a small diverse subset, which covers the whole pharmacophore space. The core set was the Technology Enabled Fragment Library I.
    Apart from the pharmacophore diversity, this set meets several medchem requirements such as the compounds contain multiple growing vectors; they are synthesizable in maximum 4 steps; and analogues are available and limited to racemates. Regarding quality: purity is higher than 95% (LC-MS), aqueous solubility preferably ≥5 mM in 5% DMSO and stability >24 h in DMSO solution. Since these compounds are derived from our Technology Enabled Library, scaffold novelty and variety are already ensured.

    – Structural diversity: Tmax=0.321
    – Pharmacophore diversity: Tmax=0.310
    – Pharmacophore coverage: 79.2%

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    4. Pharmacophore Optimised Fragment Library II

    The methodology is the same as for the Pharmacophore Optimised Fragment Library I, but the core set is much wider and contains commercial compounds, this results in even better pharmacophore coverage: 85.7%.

    – Structural diversity: Tmax=0.336
    – Pharmacophore diversity: Tmax=0.330
    – Pharmacophore coverage: 85.7%

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    5. High Fsp³ Fragment Library

    High Fsp³ fragments have been selected from Technology Enabled Fragments with Fsp³ cut-off at 0.45. ComInnex has been working on the synthesis of new sp3-rich heterocycles mainly using selective hydrogenation, but applying also spirocyclic chemistry. These core structures are also well represented in our screening library.

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    6. Covalent Minifrag Library

    Heterocyclic Electrophilic Fragment Library was developed by György M. Keserű and his team at FRAGNET-RCNS, Hungary.⁵

    84 small heterocycles are characterized with stability and reactivity data against GSH. Even though most of the heterocyclic scaffolds form non-covalent interactions with their targets Targeted Covalent Inhibitors (TCIs) that contain potential electrophilic warheads offer a novel concept for medicinal chemists. The actual design paradigm of covalent inhibitors primarily involves targeting cysteines by attaching electrophilic functional groups to known non-covalent scaffolds.

    A wide range of five- and six-membered nitrogen-containing heterocycles were collected and combined with a selection of small electrophilic warheads. Library members were then subjected to detailed characterization that included the assessment of their cysteine reactivity, specificity and aqueous stability.

    They believe that this approach would allow the precise positioning of the reactive group toward a catalytic/non-catalytic protein nucleophile in the proximity of the binding site while maintaining the key noncovalent interactions. Furthermore, electrophilic small heterocycles represent the covalent alternative of Astex’s Minifrag approach with the improved binding properties of covalent compounds. Therefore, this library represents a unique approach for covalent fragment screens.

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    7. General Fragment Library

    The ComInnex’s General Fragment Library contains 2471 compounds that fulfil the above mentioned physchem criteria: MW ≤ 250; 0≤LogP≤3; 1≤HBA≤4; 1≤HBD≤2.

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    Format

    • Download structures from the seven fragment libraries.
    • Custom select from Technology Enabled and General Libraries.
    • Compounds are available in mg or umol amounts undissolved (mostly powders, some oils), as DMSO solutions in standard or deuterated DMSO, or as dry film.
    • Delivery in vials, minitube racks, or in 96-well or 384-well plates.
    • All compounds have a minimum purity of 90% by NMR or by LC-MS/ELSD.
    • Follow-up stock is available for resupply, subject to availability.