The COVID-19 pandemic, caused by SARS-CoV-2, has underscored the urgent need for effective antiviral therapies, particularly against vaccine-resistant variants. This study investigates natural xanthone derivatives as potential inhibitors of the ACE2 receptor, a critical entry point for the virus. We computationally evaluated 91 xanthone compounds derived from Swertia chirayita , identifying two promising candidates: 8-O-[β-D-Xylopyranosyl-(1→6)-β-D-glucopyranosyl]-1,7-dihydroxy-3-methoxy xanthone (XAN71) and 8-O-[β-D-Xylopyranosyl-(1→6)-β-D-glucopyranosyl]-1-hydroxy-3,7-dimethoxy-xanthone (XAN72). Molecular docking and dynamics simulations (MDDS) were performed to assess their binding energy and stability within the ACE2 active site, comparing them to the reference inhibitor MLN-4067. The top six compounds were selected based on their docking performance, followed by Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) calculations to quantify binding affinities. Additionally, molecular electrostatic potential (MEP) analysis was conducted to visualize electron density regions relevant to binding interactions. Our results demonstrate that XAN71 and XAN72 exhibit superior binding affinities of -70.97 and − 69.85 kcal/mol, respectively, outperforming MLN-4067 (-61.33 kcal/mol). MD simulations revealed stable interactions with key ACE2 residues, primarily through hydrogen bonds and hydrophobic contacts. The Molecular Electrostatic Potential(MEP) analysis further elucidated critical electron density regions that enhance binding stability. This study establishes XAN71 and XAN72 as viable candidates for ACE2 inhibition, providing a structural basis for their development as natural xanthone-based therapeutics against SARS-CoV-2. These findings highlight the potential of targeting ACE2 with natural compounds to combat COVID-19, particularly in light of emerging viral variants.

Acute Myeloid Leukemia (AML) remains a critical therapeutic challenge, warranting the development of novel inhibitors targeting essential survival proteins such as Myeloid Cell Leukemia-1 (Mcl-1). In this purely computational study, a series of 1,2,4-triazolo[4,3-b]pyridazine derivatives were assessed for their potential as Mcl-1 inhibitors through molecular docking, molecular dynamics (MD) simulations, quantum chemical calculations, and ADMET profiling. Docking identified compounds 8f, 8j, 8k, and 8l as promising candidates, with 8l exhibiting the most favorable binding free energy (ΔG_bind = − 58.96 kcal/mol). Docking-derived inhibition constants (Ki) revealed that 8f, 8j, 8k, and 8l had Ki values of 0.31 µM, 0.32 µM, 0.35 µM, and 0.34 µM, respectively, while Sunitinib showed a slightly weaker Ki of 0.36 µM. MD simulations demonstrated increased structural stability of the protein–ligand complexes, with RMSD values ranging from 1.68 Å (8f) to 1.90 Å (8j), compared to the unbound APO structure (2.12 Å). Compound 8l maintained a low RMSD (1.71 Å) and favorable flexibility profile (RMSF = 0.89 Å), comparable to Sunitinib (RMSF = 0.76 Å). DFT analysis highlighted 8l’s high electronic reactivity, with a HOMO–LUMO gap of 3.18 eV in DMF. Although prior experimental studies confirmed 8l potent anti-AML activity (IC₅₀ = 1.5 µM), ADMET predictions revealed pharmacokinetic limitations, including low solubility and permeability. These findings position compound 8l as a compelling lead candidate for AML therapy and provide a strong foundation for future optimization aimed at improving its pharmacokinetic profile and dynamic stability. To substantiate these computational findings, we will initiate experimental validation studies involving Mcl-1 binding assays and cytotoxicity evaluation in AML cell lines. Graphical abstract

Breast cancer, a major global health challenge, is driven by aberrant receptor tyrosine kinase (RTK) signaling via epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR). This study employs a "Dynamic Scapping" workflow, integrating molecular docking, 500 ns molecular dynamics (MD) simulations, and MM/GBSA binding free energy calculations to identify natural products with potential for dual binding to EGFR (PDB: 1M17) and VEGFR (PDB: 3VHE). From ~ 20,000 natural products, virtual screening shortlisted 13 EGFR and 12 VEGFR hits, with Digitonin, Cyclamin, Vicenin-2, Glucosylorientin, and Nicotiflorin selected for EGFR, and Quercetagetin, Silychristin, Quercetin, Scutellarein, and Isorhamnetin for VEGFR, alongside references (Erlotinib, Pyrrolopyrimidine). MD simulations, conducted as single trajectories per system, revealed stable complexes (RMSD: 1.73–2.92 Å), with Digitonin, Cyclamin, and Silychristin showing binding energies (ΔG _bind : − 84.29, − 81.47, − 63.33 kcal/mol) compared to references (Erlotinib: − 43.32 kcal/mol and Pyrrolopyrimidine: − 61.63 kcal/mol). Dynamic analyses (DCCM, PCA) indicated restricted motions, while per-residue decomposition highlighted interactions with Met769 (EGFR) and Cys919 (VEGFR). The MM/GBSA calculations excluded the entropy term, potentially affecting absolute binding energies but supporting relative ranking. These computational findings suggest Digitonin, Cyclamin, and Silychristin as candidates with the potential for dual binding to EGFR and VEGFR, addressing the need for accessible treatments globally and in regions like South Africa with high incidence rates. Experimental validation is essential to confirm their functional dual modulation and inhibitory potency for breast cancer therapy. Graphical Abstract

Compound ( E )‐1‐(((4‐chloro‐2‐hydroxyphenyl)imino)methyl)naphthalen‐2‐ol ( HNC ) was prepared by the reaction between 2‐hydroxynaphthyl‐1‐carboxaldehyde and 2‐amino‐5‐chlorophenol in an equimolar ratio and obtained in moderate yield. HNC was characterized using physicochemical and various spectroscopic techniques. The slow evaporation of a hot methanolic solution of HNC resulted in the formation of the zwitterionic ketoenamine form of HNC , and denoted as HNC′ . Structurally, HNC′ comprises one naphthoxide ring bridged with one chlorophenol ring by the azomethine group, and the torsion angle between the naphthoxide and the chlorophenol ring is 11.78°, speculating a nonplanar geometry. The density functional theory (DFT) at M06‐2X/def2‐TZVP level of theory described the facile enolimine‐ketoenamine tautomerism and the highest occupied molecular orbital‐lowest unoccupied molecular orbital gap of 5.757 eV for HNC, consistent with a moderately reactive scaffold. The inhibitory potential of HNC against cyclin‐dependent kinases 2 (CDK2) was evaluated using molecular docking, molecular dynamics simulations, and molecular mechanics generalized Born surface area (MM‐GBSA) free energy calculations. Docking results showed that HNC achieved a binding score of ‐8.75 kcal/mol, slightly lower than the reference inhibitor Roscovitine (RVT), which scored ‐9.41 kcal/mol. MM‐GBSA calculations yielded ΔG _total values of ‐40.95 kcal/mol for HNC and ‐41.14 kcal/mol for RVT, suggesting comparable binding affinities. Generally, our findings pose HNC as a credible CDK2 inhibitor and tractable starting point for optimization toward selective antiproliferative agents.

Background: Invasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer and is characterized by the loss of E-cadherin resulting from alterations in the CDH1 gene. Despite accounting for approximately 10–15% of breast cancers, ILC remains understudied compared with invasive ductal carcinoma and presents unique challenges related to diagnosis, endocrine resistance, metastatic progression, and treatment. Recent molecular studies have revealed distinct genomic alterations and signaling dependencies that may provide novel therapeutic opportunities. Methods: This review summarizes current knowledge of the molecular landscape of ILC and critically examines established and emerging therapeutic targets, including PI3K/AKT/mTOR, FGFR1, ROS1, SRC/FAK, Hippo–YAP/TEAD, and estrogen receptor signaling pathways. The application of structure-based drug discovery (SBDD) approaches, including molecular docking, pharmacophore modeling, virtual screening, molecular dynamics simulations, binding free-energy calculations, and artificial intelligence-assisted methodologies, is discussed in the context of ILC drug discovery. Translational opportunities involving natural products, drug repurposing, combination therapies, and precision oncology are also evaluated. Results: Accumulating evidence indicates that CDH1 loss creates unique molecular vulnerabilities that can be therapeutically exploited. Several signaling pathways involved in tumor growth, survival, invasion, and endocrine resistance have emerged as promising therapeutic targets. Advances in structural biology, computational chemistry, and artificial intelligence have expanded opportunities for rational drug design and target prioritization. Furthermore, drug repurposing strategies, natural product-derived compounds, and multi-target therapeutic approaches offer additional avenues for accelerating the development of ILC-specific treatments. Conclusions: ILC possesses a distinct molecular architecture that supports the development of precision therapeutic strategies beyond those traditionally applied to other breast cancer subtypes. The integration of structural biology, SBDD, artificial intelligence, and translational oncology provides a promising framework for identifying and optimizing therapies targeting CDH1-loss-associated vulnerabilities. Continued efforts combining computational discovery with experimental validation are expected to accelerate the development of personalized treatment strategies and improve clinical outcomes for patients with ILC.