Ensemble Docking, MD, and MM/PBSA Identify Flavonoids as Putative Modulators of EFNB2/B3-Nipah Virus G Interaction

Nipah virus (NiV) is a highly lethal zoonotic pathogen with significant pandemic potential, for which no approved antiviral therapies are currently available. Viral entry is mediated by the interaction between the NiV attachment glycoprotein (NiV-G) and host ephrin receptors, particularly ephrin-B2 (EFNB2) and ephrin-B3 (EFNB3), making this interface an attractive therapeutic target. In this study, we evaluated a set of structurally related flavonoids, apigenin, cynaroside, and lonicerin, as potential modulators of the EFNB2–NiV-G and EFNB3–NiV-G interactions. These compounds were selected based on their structural similarity, reported antiviral activity, chemical diversity, and favorable drug-like properties. Apigenin was employed as a reference scaffold due to its well-characterized pharmacological profile and its suitability for guiding analog-based compound selection. Apigenin served as a reference scaffold for selecting structurally related flavonoids, which were analyzed through density functional theory optimization, molecular docking, pharmacokinetic and toxicity predictions, molecular dynamics simulations, and binding free energy calculations. These flavonoids demonstrated high predicted affinity for both the EFNB2–NiV-G and EFNB3–NiV-G interfaces. According to results, these compounds consistently interacted with residues known to play a critical role in receptor recognition, with special emphasis on leucine and tryptophan residues within the G–H loop. These residues are well established as key determinants in the entry process of Nipah virus (NiV) into host cells, highlighting the potential relevance of these flavonoid–protein interactions. Molecular dynamics analyses indicated that flavonoid binding reduced the affinity and the conformational flexibility at the receptor–glycoprotein interfaces and decreased the stability of the complexes. Pharmacokinetic and toxicity predictions suggested favorable drug-like properties for the flavonoids, with apigenin displaying the most balanced profile. Collectively, these results support the potential of selected flavonoids as modulators of EFNB2–NiV-G and EFNB3–NiV-G interactions and provide a rationale for their prioritization in experimental studies aimed at developing scaffolds for the modulation of viral entry against Nipah virus.