Allosteric Binding Sites: One of the most prevalent issues in drug discovery and development is the difficulty to find novel drug targets. Majority of disease-causing proteins cannot be targeted by current therapies due to the lack of a known addressable binding site. Gain Therapeutics Is able to find and target these binding sites using SEE-Tx ,its physics-based platform. SEE-Tx is able to provide quantitative predictions of druggable binding hotspots based on changes in binding free energy (ΔG).
What is the free energy change and why is it important?
The free energy determines what is going to happen at the molecular level. Molecules go where they can have a lower free energy. The change in free energy that occurs when a drug binds its target protein determines the potency of the drug. The most potent drugs experience larger changes in free energy between the unbound and bound states.
If you can predict the change in free energy, you can predict the potency of the drug. SEE-Tx predicts how much free energy a drug-like molecule could get by binding at a particular site on a protein. Therefore, we can tell if the protein is “druggable”, i.e. bind a drug molecule with high potency. We measure the difference in free energy between two states: the unbound state is the situation where protein and drug are physically separated; the bound state is the situation where the drug binds the protein at the site we have detected.
Why is free energy change predictive of a regulatory site?
Strictly speaking, we only predict sites where a drug can get tight binding. But tight binding implies that the protein becomes more stable when the drug binds to it. Therefore, druggable sites regulate protein folding.
As for regulation of the protein function (e.g. enzymatic activation or inhibition), this experiment has to be performed separately, as the computational methods are not so well suited for that. One of the first things we do after identifying active molecules, is testing its effect experimentally. Most of our compounds do not affect function, they simply stabilize the protein fold.
Gain Therapeutics SEE-Tx is the only algorithm that can quantify these regulatory sites and determine the most suitable binding sites and compounds to stabilize and restore misfolded proteins. All of the compounds in Gain Therapeutics’ development pipeline have been discovered through SEE-Tx.
Image source: https://doi.org/10.1021/jm801385d
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