Dynamix’ proprietary platform technology addresses a fundamental hurdle in drug design known as ‘induced fit’. DynamixFit™ reintroduces the dynamic properties of proteins and embeds them in a robust ‘drug discovery engine’. This 3D-based in silico technology is uniquely suitable for kinases, as it is able to identify the highly desired Type II kinase inhibitors that carry the promise of better clinical profiles.
DynamixFit™ platform technology overcomes a major hurdle in rational drug design known as the process of ‘induced fit’. As early as 1958 it was suggested that the classical ‘lock and key model’ of enzyme activity required modification. Since enzymes are flexible proteins, the 3D structures of their active sites are continuously reshaped by interactions with their substrates (or inhibitors), in a process called ‘induced fit’. Hence, the static ‘lock and key’ model had to be replaced by a dynamic model of ‘an adjustable lock and a flexible key’. While this concept has gained broad acceptance, its practical application to rational drug design has been limited by technical difficulties.
In particular, x-ray crystallography, which is the leading technology for determining the 3D structure of proteins, is quite misleading when it comes to ‘induced fit’. By its nature, crystallography produces only rigid 3D pictures, or snapshots, of protein crystals. Hence, it cannot directly show the dynamic ‘induced fit’ processes that shape and reshape the binding site. Unfortunately, straightforward molecular dynamics simulations of protein motions are still inapplicable to drug design due to time and resource limitations.
DynamixFit™ is an innovative proprietary in silico technology that extracts target-specific, dynamic, ‘induced fit’ information from multiple structures of protein-ligand complexes. DynamixFit™ identifies the dynamic parameters and motions that characterize a specific enzyme binding site, deduces how the shape of the binding site adjusts in response to ligand binding, and applies this information to drug discovery.
DynamixFit™ is embedded in Dynamix’ Drug Discovery Engine. It is used in screening for new lead compounds among more than 11,000,000 drug-like compounds stored in the Dynamix compound database. It is also used in the optimization of these leads into clinical drug candidates. Dynamix’ Drug Discovery Engine merges computational and experimental approaches into a highly cost efficient and time efficient discovery platform.
DynamixFit™ and Kinase inhibitors
Although DynamixFit™ is applicable to many classes of drug targets, it has unique advantages for discovering novel kinase inhibitors . Kinases are enzymes that play a key role in cellular signal transduction. Upon activation, most kinases undergo large functionally-significant conformation changes. For technical reasons, these conformation changes are rarely resolved in the 3D crystal structures of these kinases and have to a large extent eluded drug discoverers. DynamixFit™ technology is uniquely suitable for discovering kinase inhibitors, partcularly the highly desired Type II kinase inhibitors that carry the promise of better clinical profiles.