Cixutumumab

Cancer, an incurable global disease, demands urgent anti-cancer drug development. Marine alkaloids like Manzamine and its derivatives show promise as RSK inhibitors against cancer cell invasion. Replacing the hydrogen at the 8-position of Manzamine A with a hydroxyl group has been shown to significantly enhance its biological activity. In this article, we designed various functional group compounds (A1-A21) substituted 8-Manzamine A by docking, MM-GBSA, molecular dynamics (MD) simulation, and well-tempered metadynamics (WT-MetaD) simulations to evaluate their potential as RSK1 inhibitors. Ligands A1-A21 were docked in the RSK1 N-terminal kinase domain (PDB ID: 2Z7Q) using the Glide module. The calculation of binding energy was performed using Prime MM-GB/SA, while MD simulations were conducted with the Desmond module of Schrodinger suite 2023. Compound A5 exhibits the highest G-score (-7.01) compared to 8-Hydroxymanzamine A (-6.08). Additionally, compounds A6, A10, A12, A17, A11, A4, and A13 demonstrate increased activity against RSK1 when compared to both 8-Hydroxymanzamine A and Manzamine A. Residues LEU68, VAL76, LEU141, PHE143, LEU144, PHE150, ASP148, GLU191, and LEU194 of RSK1 protein play a key role in binding with ligands. An MD simulation of Compound A5 was carried out to explore the dynamic interactions within the protein-ligand complex. Furthermore, WT-MetaD simulations validated the docking study results and identified the most energetically favored conformations for the A5/RSK1 complex. Ligands A5, A6, A10, A12, A17, A11, A4, and A13, featuring diverse functional groups and good Glide scores, may have the potential for significant RSK1 activity and merit further development.

Succinate dehydrogenase inhibitors (SDHIs) represent one of the most important fungicide subclasses for the chemical control of plant diseases. The identification of novel SDHIs with innovative scaffolds through virtual screening is crucial for pathogenic fungi management and food security.

A novel carbothioate hit compound was identified through a hierarchical virtual screening protocol with novel β‐ketonitrile fungicidal compound as query structure. The structural optimization resulted optimal compound A12 showed good in vitro broad‐spectrum fungicidal activities against Rhizoctonia solani, Sclerotiorum sclerotiorum, Botrytis cinerea and Fusarium graminearum, with EC50 values of 4.38, 10.76, 7.69, and 10.28 μg/mL, respectively. A12 also exhibited promising in vivo protective efficacy against rice sheath blight. Scanning electron microscopy (SEM) observation and SDH enzymatic assays revealed that A12 served as a potent SDH inhibitor, with an IC50 value of 4.53 μM. Computational binding mode research demonstrated that A12 formed H‐bonds, cation‐π and T‐π interaction with SDH.

The identified optimal carbothioate compound A12 served as a potent lead compound for further structural optimization as potential agricultural SDHI fungicides. © 2025 Society of Chemical Industry.