New Pre-Plated Library of Type II Kinase Inhibitors: Ready for Your Research!

Type II kinase inhibitors are a promising class of compounds designed to target kinases in their inactive state. Unlike traditional type I inhibitors that bind to active forms,?type II inhibitors engage an extended ATP-binding site, known as the hydrophobic Deep Pocket, revealed through structural shifts in the kinase. This unique binding mode enhances specificity and affinity, reducing off-target effects and improving therapeutic precision.

The search and?development of?type II kinase inhibitors are particularly crucial in addressing drug resistance, offering innovative solutions for treating cancers and other kinase-driven diseases. This distinct mechanism opens new avenues for advancing targeted therapies.

You can explore our library by following the link: https://tinyurl.com/47wspw6j

Two Approaches, One Goal

To attain the?best outcomes in the development of a?type II kinase inhibitors library?two complementary virtual screening methods were employed in parallel:?a?shape?property-based pharmacophoric search?method and a pharmacophore-based approach.

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Shape?property-based method. RIDE (developed?at MolSoft) is a?fast 3D molecular similarity search method that utilizes Atomic Property Fields. It examines databases of compound conformers to identify molecules that are isosteric to the query, meaning they possess similar 3D configurations and atomic property distributions.

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Pharmacophore-Based Approach. This pharmacophoric modeling technique identifies and represents the essential molecular features (such as hydrogen bond donors, acceptors, and hydrophobic regions) required for a molecule to interact effectively with a specific biological target. These features are utilized to screen and design new compounds with comparable biological activity.

Library Development Process

Complexes of 13 well-known inhibitors were extracted from PKIDB and grouped based on X-ray?structure?superimposition into 6 sets. This led to the creation of 185 pharmacophore models used for virtual screening. A conformer database was built from Enamine's 3.9M in-stock compounds, generating 50 conformations per molecule. Virtual screening identified 63K and 100K prospective molecules through RIDE and pharmacophore-based methods. After filtering 6K overlapping candidates, a final library of 528 potential type II kinase inhibitors was pre-plated and is now ready for exploration.