Thitayanuwat Prawit, Hengphasatporn Kowit, Chankhamhaengdecha Surang, Shigeta Yasuteru
Department of Biology, Faculty of Science, Mahidol University, Rama VI Road, Rachadhavi, Bangkok 10400, Thailand.
Center for Computational Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan.
J Phys Chem Lett. 2025 Jun 26;16(25):6286-6292. doi: 10.1021/acs.jpclett.5c01528. Epub 2025 Jun 13.
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 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.
猪繁殖与呼吸综合征病毒（PRRSV）通过CD163受体，特别是其SRCR5结构域靶向肺泡巨噬细胞，给养猪业造成严重经济损失。然而，在这个界面上小分子抑制的分子细节仍不清楚。在此，我们首次深入了解了PRRSV/CD163-IN-1（B7）化合物如何阻断CD163-SRCR5。通过结构优化、分子动力学（MD）模拟、整体对接和片段分子轨道（FMO）计算，我们确定了一个合理的B7/CD163-SRCR5结合构象。由于晶体结构在表示构象灵活性方面的局限性，我们提出了一个MD优化的CD163-SRCR5模型，以促进对小分子重新利用文库的高效虚拟筛选。通过分析，黄芩苷成为顶级候选物，这与先前的实验证据一致。这一结果支持了黄芩苷的抗病毒活性，增强了其作为先导化合物的潜力。本研究为CD163-SRCR5处的配体识别提供了分子基础，并为设计PRRSV进入抑制剂提供了框架。
