The Rational Discovery of a Tau Aggregation Inhibitor.

ABSTRACT: Intrinsically disordered proteins play vital roles in biology, and their dysfunction contributes to many major disease states. These proteins remain challenging targets for rational ligand discovery or drug design because they are highly dynamic and fluctuate through a diverse set of conformations, frustrating structure-based approaches. To meet this challenge, we have developed protocols to efficiently identify active small molecule ligands of disordered proteins. Our approach utilizes enhanced sampling molecular dynamics and conformational analysis approaches optimized for disordered targets, coupled with computational docking and machine learning-based screens of compound libraries. By applying this protocol to an amyloid-forming segment of microtubule-associated protein tau, we success

SUBMITTER: Baggett DW 

PROVIDER: S-EPMC7021323 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature