Mechanistic Insights into PRRSV Inhibition through CD163–SRCR5 Blockade by PRRSV/CD163-IN‑1

Porcine reproductive and respiratory syndrome virus (PRRSV)
causes
severe economic losses in the swine industry by targeting pulmonary
alveolar macrophages via the CD163 receptor, particularly its SRCR5
domain. However, the molecular details of small-molecule inhibition
at this interface remain unclear. Here, we provide the first mechanistic
insights into how the PRRSV/CD163-IN‑1 (B7) compound blocks
CD163–SRCR5. Using structural refinement, molecular dynamics
(MD) simulations, ensemble docking, and fragment molecular orbital
(FMO) calculations, we identified a plausible B7/CD163–SRCR5
binding conformation. Due to the limitations of the crystal structure
in representing conformational flexibility, we proposed an MD-refined
model of CD163–SRCR5 to facilitate the efficient virtual screening
of a small-molecule repurposing library. Baicalin emerged as a top
candidate through the in silico analyses, consistent
with previous experimental evidence. This result supports baicalin’s
antiviral activity, reinforcing its potential as a lead compound.
This study provides a molecular basis for ligand recognition at CD163–SRCR5
and a framework for designing PRRSV entry inhibitors.