INVESTIGATION OF NOVEL CASPASE-1 INHIBITORS FOR THE TREATMENT OF INFLAMMATORY DISEASES EMPLOYING IN SILICO AND IN VITRO METHODOLOGY
16th INTERNATIONAL MARMARA SCIENCE AND SOCIAL SCIENCES CONGRESS, İstanbul, Türkiye, 8 - 09 Mayıs 2026, ss.49, (Özet Bildiri)
- Yayın Türü: Bildiri / Özet Bildiri
- Basıldığı Şehir: İstanbul
- Basıldığı Ülke: Türkiye
- Sayfa Sayıları: ss.49
- Marmara Üniversitesi Adresli: Evet
Özet
Although inflammation is a vital defense mechanism for the organism, dysregulation of this response plays a key role in the development of autoinflammatory and neurodegenerative diseases. At the center of this pathological process lies the activation of the Caspase-1 enzyme via the NLRP3 inflammasome complex, leading to the maturation of pro-inflammatory cytokines IL-1β and IL-18 and the induction of pyroptosis. Despite its critical role as a therapeutic target, there is currently no selective Caspase-1 inhibitor in clinical use. Therefore, the discovery of new small-molecule inhibitors with improved bioavailability represents an important research focus. In this study, a virtual screening protocol based on pharmacophore, scaffold, and electrostatic similarity was applied using 29 literature-derived reference compounds. A total of 14,884 compounds were screened by molecular docking against the Caspase-1 crystal structure, and 649 compounds with binding energies ≤ −8.0 kcal/mol were identified. After interaction-based filtering, the top 30 candidates were selected, and commercially available compounds were subjected to 250 ns molecular dynamics (MD) simulations to evaluate structural stability. MD simulations identified compound B3 as the lead molecule, maintaining stable active-site interactions throughout the simulation. Structural analysis revealed that B3 is a furocoumarin derivative exhibiting low RMSD deviation and stable interactions with key residues (Arg341, Cys285). ADME analyses indicated superior pharmacokinetic properties compared to the clinical-stage inhibitor VX-765, while experimental assays confirmed concentration-dependent Caspase-1 inhibition at the micromolar level. This work was supported by the Marmara University BAP under project number FYL-2025-12021.The numerical calculations reported in this paper were fully performed at TUBITAK ULAKBIM, High Performance and Grid Computing Center (TRUBA resources).