Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 3-13, Sesto Fiorentino (FI), I-50019, Italy.
ENEA, Portici Research Centre, DTE-ICT-HPC P.le E. Fermi, 1, Portici (NA), I-80055, Italy.
Chem Commun (Camb). 2020 Aug 4;56(62):8854-8856. doi: 10.1039/d0cc03558k.
Using a combination of enhanced sampling molecular dynamics techniques and non-equilibrium alchemical transformations with full atomistic details, we have shown that hydroxychloroquine (HCQ) may act as a mild inhibitor of important functional proteins for SARS-CoV2 replication, with potency increasing in the series PLpro, 3CLpro, RdRp. By analyzing the bound state configurations, we were able to improve the potency for the 3CLpro target, designing a novel HCQ-inspired compound, named PMP329, with predicted nanomolar activity. If confirmed in vitro, our results provide a molecular rationale for the use of HCQ or of strictly related derivatives in the treatment of Covid-19.
我们采用增强采样分子动力学技术和全原子细节的非平衡化学转化相结合的方法，表明羟氯喹（HCQ）可能是一种轻度抑制剂，可抑制 SARS-CoV2 复制的重要功能蛋白，其效力按 PLpro、3CLpro、RdRp 的顺序递增。通过分析结合态构象，我们能够提高 3CLpro 靶标抑制活性，设计了一种新型受 HCQ 启发的化合物，命名为 PMP329，具有预测的纳摩尔活性。如果在体外得到证实，我们的研究结果为使用 HCQ 或严格相关的衍生物治疗 COVID-19 提供了分子依据。
