Hantavirus ANDV Glycoprotein Gc: Multi-Site Computational Analysis of Remdesivir Binding Under pH-Dependent Fusion Conditions

Hantaviruses are emerging zoonotic pathogens responsible for hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), diseases associated with substantial mortality and limited antiviral treatment options. Andes virus (ANDV), a highly pathogenic New World hantavirus, utilizes the glycoprotein complex composed of Gn and Gc proteins to mediate host-cell entry and membrane fusion. The Gc glycoprotein undergoes pH-dependent structural rearrangements during endosomal trafficking, making it an attractive therapeutic target. In the present study, a comprehensive molecular docking analysis of Remdesivir against multiple functional regions of the Andes virus glycoprotein Gc was performed using AutoDock Vina under physiologically relevant pH conditions (7.4, 5.5, and 4.6). Five structurally and functionally important regions were investigated, including the fusion-loop pocket (Region 1), Gc homodimer interface (Region 2), pH-sensing interface (Region 3), GnB–Gc stem accommodation interface (Region 4), and conserved aromatic groove stabilization region (Region 5). Remdesivir exhibited strong multi-site binding with affinities ranging from −9.1 to −7.0 kcal/mol. These findings suggest that Remdesivir may interfere with viral fusion machinery through simultaneous constitutive and pH-sensitive mechanisms. The study provides mechanistic insights into hantavirus fusion regulation and highlights the potential value of multi-site antiviral targeting strategies against emerging RNA viruses.