Small molecule alternatives to therapeutic antibodies
Jamming of a tiny nail into a 'hinge' can induce a large effect on the size of the opening for a door
Structurally invisible and functionally invincible flexible loops 'hingez' at work
Tackling New Frontiers
Developing Small Molecule Drugs to Disrupt Protein-Protein Interactions
About 20,000 protein-coding genes in the human genome.
Most of these proteins carry out their functions by interacting with other proteins (i.e. protein-protein interaction).
More than 600,000 protein-protein interactions are estimated in humans.
A large number of human diseases are caused by abnormal protein-protein interactions.
Developing a small molecule modulator of protein-protein interactions is the biggest challenge in drug discovery today.
We have developed a method that will revolutionize small molecule discovery to disrupt protein-protein interactions.
Imagination and Innovation together
Proteins are dynamic and undergo constant conformational changes. Structurally, proteins contain rigid areas interspersed with flexible areas. This structural duality confers plasticity to proteins. In most drug discovery approaches, the rigid areas are targeted. More importantly, flexible areas are not targeted because they are not visible in crystal structures and lack well-defined coordinates.
Our technology utilizes specific flexible areas, called 'hinges,' to develop small molecule, 'a wedge,' to allosterically deform protein-protein interaction interfaces; as a result, disrupt protein-protein interactions.
The human PD-L1/2 crystal structures were analyzed for hinge points conformers with a disrupted PD1/PDL1 binding surface. Three lead-like molecules are under investigation to generate leads.
PCSK9 conformations that are incapable of interacting with the EGF-AB domain of LDLR were selected and used for hit identification and validation. The validated hits represent three distinct chemical series.
Flexible areas of PD1 crystal structures were analyzed for hinge points conformers. The hinge points were engaged with small molecules to disrupt interactions between PD1 and PD-L1. Two validated hits represent distinct chemical series are being optimized.
Sub-type specific inhibitors
Hinge technology is used to identify, test, and validate novel sub-type specific JAK1/3 kinase inhibitors using direct binding and cellular assays. The identified inhibitors are being developed for the treatment of inflammatory diseases.
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