Exploiting conformational dynamics in drug discovery: design of C-terminal inhibitors of Hsp90 with improved activities.

ABSTRACT: The interaction that occurs between molecules is a dynamic process that impacts both structural and conformational properties of the ligand and the ligand binding site. Herein, we investigate the dynamic cross-talk between a protein and the ligand as a source for new opportunities in ligand design. Analysis of the formation/disappearance of protein pockets produced in response to a first-generation inhibitor assisted in the identification of functional groups that could be introduced onto scaffolds to facilitate optimal binding, which allowed for increased binding with previously uncharacterized regions. MD simulations were used to elucidate primary changes that occur in the Hsp90 C-terminal binding pocket in the presence of first-generation ligands. This data was then used to design ligan

SUBMITTER: Moroni E 

PROVIDER: S-EPMC4123794 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature