Hormone-dependent breast cancer, particularly in its treatment-resistant forms, remains a significant therapeutic challenge. In this study, we applied a fully computational strategy to design steroid-based compounds capable of simultaneously targeting three key receptors involved in disease progression: progesterone receptor (PR), estrogen receptor alpha (ER-α), and HER2. Using a robust 3D-QSAR model (R² = 0.86; Q²_LOO = 0.86) built from 52 steroidal structures, we identified molecular features associated with high anticancer potential, specifically increased polarizability and reduced electronegativity. From a virtual library of 271 DFT-optimized analogs, 31 compounds were selected based on predicted potency (pIC₅₀ > 7.0) and screened via molecular docking against PR (PDB 2W8Y), HER2 (PDB 7JXH), and ER-α (PDB 6VJD). Seven candidates showed strong binding affinities (ΔG ≤ −9 kcal/mol for at least two targets), with Estero-255 emerging as the most promising. This compound demonstrated excellent conformational stability, a robust hydrogen-bonding network, and consistent multitarget engagement. Molecular dynamics simulations over 100 nanoseconds confirmed the structural integrity of the top ligands, with low RMSD values, compact radii of gyration, and stable binding energy profiles. Key interactions included hydrophobic contacts, π–π stacking, halogen–π interactions, and classical hydrogen bonds with conserved residues across all three targets. These findings highlight Estero-255, alongside Estero-261 and Estero-264, as strong multitarget candidates for further development. By potentially disrupting the PI3K/AKT/mTOR signaling pathway, these compounds offer a promising strategy for overcoming resistance in hormone-driven breast cancer. Experimental validation, including cytotoxicity assays and ADME/Tox profiling, is recommended to confirm their therapeutic potential.

Oropouche virus (OROV), an emerging orthobunyavirus of increasing public health concern in the Americas, currently lacks approved antiviral therapies. In this study, we employed a structure-based in silico approach to identify natural antiviral scaffolds capable of targeting the Gc glycoprotein, a class II fusion protein essential for host membrane fusion and viral entry. A library of 537 plant-derived compounds was screened against the Gc head domain (PDB ID: 6H3X) through molecular docking and redocking, followed by 100-nanosecond molecular dynamics simulations, MM-PBSA free energy calculations, and ADMET profiling. Curcumin and Berberine emerged as standout candidates. Curcumin demonstrated a balanced profile, with stable binding (−38.14 kcal/mol), low backbone RMSD (1.82 Å), and consistent radius of gyration (Rg ~ 18.8 Å), suggesting strong conformational stability and compactness of the protein–ligand complex. Berberine exhibited the most favorable binding energy (−13.10 kcal/mol) and retained dynamic stability (RMSD 1.86 Å; Rg ~ 19.0 Å), though accompanied by predicted cytotoxicity that may require structural refinement. Both compounds induced reduced residue-level fluctuations (RMSF < 2.5 Å) in functionally critical regions of the Gc protein, consistent with a mechanism of action that involves stabilization of the prefusion conformation and interference with the structural transitions required for viral entry. These findings identify curcumin and berberine as promising scaffolds for anti-OROV drug development and offer a rational foundation for future experimental validation targeting viral fusion mechanisms.

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.