Fragment optimization for GPCRs by molecular dynamics free energy calculations: Probing druggable subpockets of the A _2A adenosine receptor binding site.

ABSTRACT: Fragment-based lead discovery is becoming an increasingly popular strategy for drug discovery. Fragment screening identifies weakly binding compounds that require optimization to become high-affinity leads. As design of leads from fragments is challenging, reliable computational methods to guide optimization would be invaluable. We evaluated using molecular dynamics simulations and the free energy perturbation method (MD/FEP) in fragment optimization for the A_2A adenosine receptor, a pharmaceutically relevant G protein-coupled receptor. Optimization of fragments exploring two binding site subpockets was probed by calculating relative binding affinities for 23 adenine derivatives, resulting in strong agreement with experimental data (R² = 0.78). The predictive power of

SUBMITTER: Matricon P 

PROVIDER: S-EPMC5526870 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature