Eccentric PPI Library

Description

ChemDiv’s eccentric PPI library contains 12,103 compounds

The eccentric PPI (Protein-Protein Interaction) library represents a cutting-edge collection of small molecule compounds designed specifically to target and modulate protein-protein interactions, a burgeoning area in drug discovery. Protein-protein interactions are crucial for numerous biological processes and pathways, making them attractive targets for therapeutic intervention. However, their typically large and flat interaction surfaces pose unique challenges for small molecule drug design. The eccentric PPI library addresses these challenges head-on, employing innovative chemistries and molecular frameworks to create molecules capable of effectively binding to and modulating these complex interfaces. This collection is curated to include compounds with diverse structural features, enhancing the likelihood of identifying potent and selective inhibitors or stabilizers of PPIs.

Each compound within the eccentric PPI library has been meticulously selected based on its potential to interact with key hotspots and allosteric sites involved in PPIs, leveraging structural biology insights and advanced computational modeling techniques. The library encompasses a range of molecules, from those targeting well-characterized interactions involved in cancer, neurodegenerative diseases, and inflammatory conditions, to pioneering efforts aimed at previously undruggable targets. By focusing on the modulation of protein-protein interactions, the library opens new avenues for the development of therapeutics with novel mechanisms of action. Furthermore, the eccentric PPI library is continuously evolving, with ongoing research and screening efforts aimed at expanding its diversity and enhancing the pharmacological properties of its compounds, ensuring it remains at the forefront of drug discovery innovation.

The biological activity of molecules is inherently linked to their three-dimensional (3D) structure, underscoring the critical role that the spatial arrangement plays in their function. When considering the diversity of eccentric PPI Library, the molecular shape diversity stands as a primary indicator of its overall functional breadth. While "diversity" may seem like a subjective concept, the literature consistently highlights six principal components of structural diversity that are crucial for enhancing the library's potential in drug discovery:

1. Scaffold Diversity: This refers to the inclusion of a wide array of distinct molecular frameworks within the library, offering a variety of core structures for interaction with biological targets.
2. Functional Group Diversity: It encompasses the variety of functional groups present within the compounds, which can significantly influence the molecules' reactivity and interaction capabilities.
3. Appendage Diversity (Substituent or Building-Block Diversity): This aspect captures the variation in structural elements attached to a common scaffold, enriching the library with a multiplicity of side chains and modifications.
4. Stereochemical Diversity: The variation in the spatial arrangement of atoms, particularly those that could interact with macromolecules, adds a critical layer of diversity, impacting binding affinity and specificity.
5. Conformational Diversity: This involves the inclusion of molecules that can adopt multiple conformations, thereby increasing the chances of finding a conformation that is optimal for target interaction.
6. Chain Diversity: The presence of various distinct chains, particularly important when the scaffold does not uniquely define the molecule, further diversifies the interaction possibilities.

Compounds from the eccentric PPI library serve as a valuable resource for drug discovery by targeting the complex interfaces of protein-protein interactions, which are pivotal in numerous biological processes and disease pathways. These small molecules are designed to modulate PPIs, offering potential therapeutic strategies for conditions where traditional small molecule drugs and biologics may fall short. By interfering with or stabilizing specific protein interactions, these compounds can disrupt or enhance cellular signaling pathways involved in diseases such as cancer, neurodegenerative disorders, and inflammatory conditions. The diversity and specificity of the molecules within the eccentric PPI library enable researchers to explore novel therapeutic targets, overcome drug resistance mechanisms, and develop drugs with new mechanisms of action, thereby expanding the horizon of drug discovery and providing new avenues for the development of highly effective and targeted treatments.

Publications

Tsaloev A., Ilyin A., Tkachenko S., Ivachtchenko A., Kravchenko D., Krasavin M. Cyclic products of the Ugi reaction of aldehydo and keto carboxylic acids: chemoselective modification. Tetrahedron Letters. 2011, 52: 1800–1803.


Kysil V., Khvat A., Tsirulnikov S., Tkachenko S, Williams C., Churakova M., Ivachtchenko A. General Multicomponent Strategy for the Synthesis of 2-Amino-1,4-diazaheterocycles: Scope, Limitations, and Utility. European Journal of Organic Chemistry. 2010; 1525–1543.


Kysil V.M., Khvat A., Tsirulnikov S., Tkachenko S., Ivachtchenko A. Multicomponent approach to unique 1,4-diazepine-2-amines. Tetrahedron Letters. 2009; 50(24): 2854-2856.


Balakin K.V., Ivanenkov Y.A., Tkachenko S.E., Kiselyov A.S., Ivachtchenko A.V. Regulators of chemokine receptor activity as promising anticancer therapeutics. Current Cancer Drug Targets. 2008; 8(4): 299-34.


Kiselyov A.S., Tkachenko S.E., Balakin K.V., Ivachtchenko A.V. Small-molecule modulators of Hh and Wnt signaling pathways. Expert Opinion on Therapeutic Targets. 2007; 11(8): 1087-1101.


Savchuk N.P., Tkachenko S.E., Balakin K.V. Design of pGPCR-targeted Libraries. In Rognan D., ed. Ligand Design for G Protein-coupled Receptors. Methods and Principles in Medicinal Chemistry (Volume 30). Weinheim: Wiley VCH. 2006, pp. 137-164.


Kysil V., Tkachenko S., Khvat A., Williams C., Tsirulnikov S., Churakova M., Ivachtchenko A. TMSCl-Promoted Isocyanide-Based MCR of Ethylenediamines: an Efficient Assembling of 2-Aminopyrazine Core. Tetrahedron Letters, 2007; 48(36): 6239-6244.