Ornob, A. | bioRxiv Science

bioRxiv2026

Ribociclib as a Potential Multi-Target Inhibitor of Pro-Inflammatory Cytokines: An In Silico Investigation

Ribociclib, a selective cyclin-dependent kinase (CDK) 4/6 inhibitor, is approved as a first-line therapy for HR-positive/HER2-negative advanced breast cancer. Emerging evidence suggests that Ribociclib may exert immunomodulatory effects. However, its role in cytokine regulation remains largely unexplored. This study presents a comprehensive in silico investigation of Ribociclibs interactions with eight key pro-inflammatory cytokines--IL-6, TNF-, IL-17A, IL-17F, IL-17A/F, IL-1{beta}, MCP-1, and IFN-{gamma}. Computational assessments included molecular docking, molecular dynamics (MD) simulations, MM-GBSA binding free energy calculations, principal component analysis (PCA), and dynamic cross-correlation matrix (DCCM) analyses. Molecular docking and MD simulations indicated strong and stable complex formation with TNF-, IL-6, MCP-1, IL-1{beta}, and IL-17A/F. MM-GBSA results further showed that Ribociclib formed the most stable complexes with IL-17A/F ({Delta}Gbind = -25.94 kcal/mol) and MCP-1 ({Delta}Gbind = -25.88 kcal/mol), comparable to binding with the CDK-6 ({Delta}Gbind = -36.23 kcal/mol) control protein. PCA and DCCM analyses further supported the stabilizing influence of Ribociclib on these cytokine conformations. Moderate interactions were observed with TNF-, IL-6, and IFN-{gamma}. Collectively, these findings suggest that Ribociclib may function as a multi-target inhibitor capable of modulating diverse inflammatory pathways, providing a computational foundation for its repurposing as a cost-effective anti-inflammatory therapeutic candidate.

pharmacology and toxicology↗

bioRxiv2024

Deep learning based predictive modeling to screen natural compounds against TNF-alpha for the potential management of Rheumatoid Arthritis: Virtual screening to comprehensive in silico investigation

Rheumatoid arthritis (RA) affects an estimated 0.1% to 2.0% of the worlds population, leading to a substantial impact on global health. The adverse effects and toxicity associated with conventional RA treatment pathways underscore the critical need to seek potential new therapeutic candidates, particularly those of natural sources that can treat the condition with minimal side effects. To address this challenge, this study employed a deep-learning (DL) based approach to conduct a virtual assessment of natural compounds against the Tumor Necrosis Factor-alpha (TNF-) protein. TNF- stands out as the primary pro-inflammatory cytokine, crucial in the development of RA. Our predictive model demonstrated appreciable performance, achieving MSE of 0.6, MAPE of 10%, and MAE of 0.5. The model was then deployed to screen a comprehensive set of 2563 natural compounds obtained from the Selleckchem database. Utilizing their predicted bioactivity (pIC50), the top 128 compounds were identified. Among them, 68 compounds were taken for further analysis based on drug-likeness analysis. Subsequently, selected compounds underwent additional evaluation using molecular docking (< - 8.7 kcal/mol) and ADMET resulting in four compounds posing nominal toxicity, which were finally subjected to MD simulation for 200 ns. Later on, the stability of complexes was assessed via analysis encompassing RMSD, RMSF, Rg, H-Bonds, SASA, and Essential Dynamics. Ultimately, based on the total binding free energy estimated using the MM/GBSA method, Imperialine, Veratramine, and Gelsemine are proven to be potential natural inhibitors of TNF-.

bioinformatics↗