Computational research of Belnacasan and new Caspase-1 inhibitor on cerebral ischemia reperfusion injury

Abstract

Cerebral ischemia-reperfusion injury is one of the most severe diseases in terms of mortality and disability, which seriously threatens human life and health. In clinical treatment, drug thrombolysis or mechanical interventional thrombolysis are used to quickly restore the blood supply of ischemic brain tissue. But with the rapid recovery of blood flow, complex pathophysiological processes such as oxidative stress and inflammation will further aggravate brain tissue damage, namely cerebral ischemia-reperfusion injury, for which there is no effective treatment. Recent studies have shown that the medical community has paid the role of inflammation and pyroptosis in cerebral ischemia-reperfusion injury more and more attention. And Caspase-1 was found to play a vital role in regulating inflammation pathways and pyroptosis in many inflammation-associated diseases, especially in cerebral ischemiareperfusion injury. Not only that, Caspase-1 inhibitors have been shown to reduce the damage of cerebral ischemia-reperfusion injury by inhibiting inflammation and pyroptosis. And the Caspase-1 inhibitor, Belnacasan, has been proved to modify the active site of Caspase-1 and lead to the blocking of Caspase-1, thus correlating with tissue protection of inflammatory diseases in animal models. Therefore, it's essential to screen and design potential Caspase-1 inhibitors to reduce cerebral ischemia-reperfusion injury and protect brain function by reducing inflammation and pyroptosis, which provides a new idea for clinical treatment of the cerebral ischemia-reperfusion injury. This study applied a group of computer-aided technology, such as Discovery Studio 4.5, Schrodinger, and PyMol, to screen and assess potential Caspase-1 inhibitors. Moreover, the ADME (absorption, distribution, metabolism, excretion) and TOPKAT (Toxicity Prediction by Computer Assisted Technology) molecules of Discovery Studio 4.5 were conducted to evaluate molecules' pharmacological and toxicological features. Then, precise molecular docking was applied to assess the binding mechanism and affinity between Caspase-1 and selected compounds. Besides, molecular dynamics simulations were performed to determine the stability of ligand-receptor complexes in the natural environment. In summary, this study lists promising drug candidates and their pharmacological properties, promoting the development of Caspase-1 inhibitors and deepening the understanding of the interaction between inhibitors and Caspase-1.

Mapping the Binding Interactions between Human Gasdermin D and Human Caspase-1 Using Carbene Footprinting

“…The addition of VRT-043198 induced a single labeling reduction on the p20 subunit at peptide 279–286 (Figures , S25, and S26A) and three significant labeling reductions on the p10 subunit, including at peptides 342–352, 375–383, and 384–391 (Figures and S27A). Pleasingly, when mapped to the Caspase-1/VRT-043198 crystal structure (PDB 6PZP), these masking events localized to the ligand binding site, suggesting that despite the absence of the catalytic residue, the metabolite was binding to Caspase-1 (C285A) in a similar region to that of wildtype Caspase-1 . MS/MS was again utilized to provide higher resolution labeling information on masked peptides.…”

“…Pleasingly, when mapped to the Caspase-1/VRT-043198 crystal structure (PDB 6PZP ), these masking events localized to the ligand binding site, suggesting that despite the absence of the catalytic residue, the metabolite was binding to Caspase-1 (C285A) in a similar region to that of wildtype Caspase-1. 29 MS/MS was again utilized to provide higher resolution labeling information on masked peptides. CID fragmentation showed consistent fragmentation patterns, and similar residue-level labeling, to those observed in the GSDMD/Caspase-1 labeling study (see Section 2.2).…”

Rhubarb free anthraquinones improved mice nonalcoholic fatty liver disease by inhibiting NLRP3 inflammasome

“…The role of these effective RFAs, rhubarb and YCHD in improving MCD diet induced mice NAFLD by inhibiting NLRP3 inflammasome was explored. NAFLD mice established by MCD diet for 9 weeks were administered by these effective RFAs, rhubarb and YCHD as well as inflammasome inhibitors MCC950 [ 34 ] and VX765 [ 35 ]. All these drugs improved liver function including ALT (Fig.…”