Designing small molecules to target cryptic pockets yields both positive and negative allosteric modulators.

ABSTRACT: Allosteric drugs, which bind to proteins in regions other than their main ligand-binding or active sites, make it possible to target proteins considered "undruggable" and to develop new therapies that circumvent existing resistance. Despite growing interest in allosteric drug discovery, rational design is limited by a lack of sufficient structural information about alternative binding sites in proteins. Previously, we used Markov State Models (MSMs) to identify such "cryptic pockets," and here we describe a method for identifying compounds that bind in these cryptic pockets and modulate enzyme activity. Experimental tests validate our approach by revealing both an inhibitor and two activators of TEM β-lactamase (TEM). To identify hits, a library of compounds is first virtually screened aga

SUBMITTER: Hart KM 

PROVIDER: S-EPMC5453556 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature