Structural Basis for Binding of Allosteric Drug Leads in the Adenosine A₁ Receptor.

ABSTRACT: Despite intense interest in designing positive allosteric modulators (PAMs) as selective drugs of the adenosine A₁ receptor (A₁AR), structural binding modes of the receptor PAMs remain unknown. Using the first X-ray structure of the A₁AR, we have performed all-atom simulations using a robust Gaussian accelerated molecular dynamics (GaMD) technique to determine binding modes of the A₁AR allosteric drug leads. Two prototypical PAMs, PD81723 and VCP171, were selected. Each PAM was initially placed at least 20 Å away from the receptor. Extensive GaMD simulations using the AMBER and NAMD simulation packages at different acceleration levels captured spontaneous binding of PAMs to the A₁AR. The simulations allowed us to identify low-energy bi

SUBMITTER: Miao Y 

PROVIDER: S-EPMC6237911 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature