Protein-protein interactions (PPIs) are among the most attractive targets for modern drug design and development. However, this field of interactions is not well explored, and there are no universal features for all proteins involved in it. Several dozens of protein pairs have been thoroughly investigated so far, and their crystal structures have revealed the mechanism of the tight connection between interfaces. These investigations present a hard task consuming too much time and effort, but they can be facilitated by the development of a fragment-based screening library focused on the inhibition of protein-protein interactions.
Fragment-based drug discovery (FBDD) showed to be a better approach for the design of novel PPIs modulators in comparison with HTS as the PPI interface often consists of discontinuous hot-spots. Nuclear magnetic resonance (NMR), X-ray crystallography, surface plasmon resonance (SPR), and mass spectroscopy (MS) can be utilized for discovery and validation of theory.
Formulation of a set of descriptors and ranking mechanisms of arraying fragments based on our thorough analysis of published data enabled us to design the proprietary PPI Fragment Library of 8,300 readily-available fragment-like compounds for PPI-related FBDD. This Screening Set intersect both fragment and PPI inhibitors chemical spaces.
The compound selection can be customized based on your requirements, cherry picking is available.
Please, contact us at orders@lifechemicals.com for any additional information and price quotations.
Compound selection
It was shown that PPI inhibitors are typically larger and more lipophilic than inhibitors of more standard binding sites of most proteins [1]. That is why PPI fragments have TPSA values higher than it was generally claimed when practicing a common approach to fragment-based drug design. The same applies to the molecular weight of compounds that should be between 250 and 450 Da. Thus, such compounds cannot fit a standard Rule of Three, usually used for selection of fragments.
| Parameter | MW | ClogP | TPSA | RotBonds | HbD | HbA | Fsp3 | Hydrophobic cores | Rings | npr1+npr2 |
| Range | 250 - 450 | 2.5 - 4.5 | < 75 Å2 | ≤8 | ≤ 3 | ≤ 5 | > 0.4 | 1 - 5 | > 0 | > 1.07* |
Figure 1. Physicochemical parameter values of the PPI Fragment Library
It was found that small molecules targeting PPI have highly hydrophobic cores within peripheral lipophilic substituents [2]. To enhance selectivity, we have proposed very reasonably chosen hydrophobic and more spatial structures (sp³-enriched).
The main result of the compilation of the features mentioned above is a special chemical space for compounds with a common function of PPI interaction inhibition. One more detail that characterizes PPI fragments is the principal moment of inertia (PMI). Mean values of npr1 = 0.24, npr2 = 0.89 show the distribution of compounds in 3D space and evaluate 3D-shape diversity. Finally, the compounds were passed through the PAINS filter.
Representative fragment compounds from PPI Fragment Library
References
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- Magee, T. V. Progress in discovery of small-molecule modulators of protein-protein interactions via fragment screening. Bioorg. Med. Chem. Lett. 25, 2461–2468 (2015).
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