PPI Fragment Library

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 library focused on the inhibition of protein-protein interactions.

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 Life Chemicals PPI Fragment Library. It is a collection of 3,900 readily available small-molecule compounds for FBDD that intersect both fragment and PPI inhibitors chemical spaces.

Parameter

Range

MW

150 - 450

ClogP

2.5 - 4.5

Fsp³

> 0.4

TPSA

< 75 Å2

Rotatable bonds

≤ 8

H-donors

≤ 3

H-acceptors

≤ 5

Hydrophobic cores

1 - 6

 

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.

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 = 0.28, npr2 = 0.88 show the distribution of compounds in 3D space and evaluate 3D-shape diversity [3]. Finally, the compounds were passed through the PAINS filter.

Examples of fragments focused on inhibition of protein-protein interactions

References

  1. Reynes C. et al. PLoSComput Biol. 2010, Mar 5; 6 (3): e1000695.
  2. Fry D. C. Biopolymers 2006, 84, 535–52.
  3. Carr R. A. et al. Drug Discov. Today 2005, 10, 987–992.
  4. Erlanson, D. A.; Jahnke, W.; Mannhold, R. Wiley-VCH, 2016, 528 pp.[1] 
  5. Rosell M, Fernández-Recio J. Expert Opin Drug Discov. 2018 Apr;13(4):327-338.
  6. Kaczor AA, Bartuzi D. et al. Methods Mol Biol. 2018;1762:285-305.
  7. Price A, Howard S, Cons BD. Essays Biochem. 2017 Nov 8;61(5):475-484.