Targeting S100A9-EF Ca²⁺ sequestration with natural compounds: insights from molecular docking and molecular dynamics simulation
摘要
The Ca²⁺-binding proteins S100A8 and S100A9, classified as damage-associated molecular patterns (DAMPs), contribute to rheumatoid arthritis (RA) pathogenesis via pattern recognition receptors (PRRs). Our previous study demonstrated that S100A9 exhibited a higher affinity for PRRs receptors in the presence of Ca2+ ions. The study aims to identify natural compounds that block Ca²⁺ sequestration by the EF-hand loops of S100A9 to inhibit its activity via computational approaches such as network analysis, docking, drug-likeness, ADMET and molecular dynamics simulation (MD). Network analysis revealed S100A9 interacts most strongly with S100A8, followed by TLR4, IL-1β, and NLRP3. Gene ontology revealed the critical role of the target genes in leukocyte aggregation, LPS receptor complex, NLRP3 inflammasome complex, and TLR4 binding. Screening of 662 phytoconstituents through molecular docking, drug-likeness, and toxicity analysis identified grossamide as a potential candidate. Molecular docking analysis showed that grossamide exhibited the lowest binding energy of -8.0 kcal/mol. NMA analysis showed the flexibility of the EF-hand domains and rigid nature of the helices indicating its structural integrity. The 100 ns MD showed that the grossamide–S100A9 EF complex exhibited an equilibrated RMSD trajectory. At the same time, the RMSF, contact plot, and interaction fractions indicating the interactions of S100A9-EF domains with grossamide, characterized by minimal fluctuations, stable hydrogen bond formation, and sustained contact throughout the simulation. Grossamide emerges as a potential therapeutic candidate capable of preventing Ca²⁺ sequestration by S100A9-EF hand motifs, thereby inhibiting dimer formation and related signaling pathways. However, further in vitro and in vivo studies are required to establish the safety and therapeutic efficacy of grossamide in RA.