SYSTEMS AND METHODS FOR IDENTIFYING POSITIVE ALLOSTERIC MODULATORS OF ENZYMES TO ENHANCE ACTIVITY

摘要

Methods and systems are provided for identifying positive allosteric modulators of proteins. Small compounds that enhance enzyme activity by binding to an allosteric site are identified, by analysis of biophysical and dynamics data for the target protein. More specifically, the present disclosure is directed to identifying and enhancing the dynamics and energetic behavior of distal surface regions that affect catalytic activity. These allosteric regions are identified and ranked for the impact on enzyme activity, based on the transfer of energy from the surface regions to the active site. Methods are described for computationally screening of chemical compounds to determine a binding energy between each chemical compound and each potential allosteric site. Modifications to the chemical compounds can be made to improve the binding energy, increasing the transfer of energy into the active site, and increasing the number of conformations in the functionally important conformations sub-states. Chemical compounds are selected as top ranking positive allosteric modulators based on ability to modify the conformations of the protein to enhance enzymatic activity.