The emergence of multidrug-resistant Neisseria gonorrhoeae has intensified the need for innovative therapeutic strategies. One promising but underexplored target is the Hfq protein, a key regulator in bacterial stress response and pathogenesis. In this study, we employed a computer-aided drug discovery approach to screen phytochemicals from traditionally used anti-gonorrheal plants for their potential to inhibit Hfq. Molecular docking identified several compounds, including Hellebrigenin 3-acetate, Carpaine, β-amyrin, α-amyrin, Rosarin, Oleanolic acid, and Epigallocatechin 3-O-gallate, with binding affinities surpassing that of the reference drug, Ceftriaxone. Molecular dynamics simulations revealed that Carpaine and Oleanolic acid formed the most stable Hfq complexes, exhibiting low RMSD values (0.73 nm and 0.66 nm) and compact Rg profiles (~ 1.4 nm), indicating strong structural stabilization. ADMET analysis suggested moderate intestinal absorption and oral bioavailability, though some compounds showed risks of liver toxicity and CYP2D6 inhibition. Carpaine demonstrated the most favorable binding free energy and prolonged systemic retention, making it an up-and-coming lead candidate. Importantly, evolutionary analysis confirmed the conservation of the Hfq active site, further supporting its viability as a therapeutic target. These findings reveal the potential of plant-derived compounds, particularly Carpaine and Oleanolic acid, as novel Hfq inhibitors, providing a strong foundation for future experimental validation and the development of alternative therapies against multidrug-resistant N. gonorrhoeae.

Research efforts for pancreatic cancer (PC) therapy has led to investigations of numerous therapeutic targets, yet there are still limited efficacy outcomes. In 2021, the annual PC cases of 508,533 resulted in mortality of 505,752 for both sexes according to GLOBOCAN. In order to address this burden, enhancer of zeste homolog 2 (EZH2); an epigenetic regulator implicated in various cancers, has been an attractive target, due to promising tumor-suppressive effects in both preclinical and clinical studies. This effect was observed from drugs that have strong affinity towards EZH2, but there is need to improve the structural moieties for better interaction towards this protein. In this study, we employed a structure-based drug discovery approach using CHEESE webserver for rapid ligand-based screening to identify and evaluate phytochemical derivatives for their potential to bind EZH2. Five phytochemicals, namely Moracin P, Naringenin 5-rhamnoside, Pinostrobin 5- glucoside, Phytocassane A, and Sakuranin with best performance against EZH2-PPARs from our previous study was used to generate top ten new derivatives each. The derivatives were subjected to molecular docking, pharmacokinetic, and toxicity predictions. The top-performing derivative interacting with EZH2 were further subjected to ADMET profiling with favorable pharmacokinetic, toxicity properties, and meeting key drug-likeness criteria. Molecular docking results revealed that several derivatives of Moracin P, Naringenin 5-rhamnoside, and Phytocassane A displayed higher predicted binding affinities (− 6.4 to − 8.2 Kcal/mol) compared to the parent template previously assessed for EZH2, engaging critical residues through hydrogen bonds and hydrophobic interactions. Molecular dynamic simulation (MDS) over 200 ns further confirmed the stability of selected protein-ligand complexes, with Moracin_P7 and Pinostrobin 5-glucoside_5 exhibiting high degrees flexibility within the first 100 ns, but remained stable for the last 100 ns, while contact analysis highlighted consistent interactions with the active site residues Gln653, Asp657, Asp664, Ser669, Asn673, Phe678, His711 and Tyr731. Conclusively, these findings provide evidence that CHEESE webserver is suitable to generate phytochemical derivatives that can be explored as feasible candidate in EZH2 inhibitory study and laying the groundwork for further in-vitro and in-vivo validation.