Novel Phosphodiesterase‑2 Inhibitors Discovered via Structure-Based Virtual Screening Targeting the Allosteric GAF‑B Domain.
TL;DR
It is demonstrated that incorporation of binding mode analysis into virtual screening workflows can substantially improve hit identification and may provide a valuable strategy for future virtual screening campaigns against PDE2 and other therapeutic targets.
Abstract
Phosphodiesterase-2 (PDE2) regulates intracellular cAMP and cGMP signaling and is an important therapeutic target. In this study, we performed the first virtual screening campaign targeting the allosteric GAF-B domain of PDE2 to identify novel allosteric inhibitors. Unlike conventional virtual screening methods based mainly on calculated binding energies, our approach incorporated binding mode analysis to rerank the top 5000 compounds according to the number of hydrogen-bonding and π-π stacking interactions with GAF-B residues. Experimental testing identified various novel PDE2 inhibitors, including compound 1 (IC5 0 = 0.77 μM) selective for PDE2 over other PDE isoforms. The reranking strategy yielded high hit rates of 62%, 51%, 29%, and 14% at inhibition thresholds of 25%, 30%, 40%, and 50%, respectively. These findings demonstrate that incorporation of binding mode analysis into virtual screening workflows can substantially improve hit identification and may provide a valuable strategy for future virtual screening campaigns against PDE2 and other therapeutic targets.