Endothelial soluble guanylyl cyclase enzyme inhibitors as novel target for treatment of sepsis related hypotension

Background Sepsis-related hypotension is a life-threatening condition due to systemic infection leading to widespread inflammation and blood vessel dilation. This can cause a dramatic drop in blood pressure, impairing blood flow to vital organs and potentially leading to organ failure and death. NO was recognized as a significant factor in sepsis in 1990 and became an important therapeutic target. NO plays a dual role in sepsis, exhibiting both beneficial and harmful effects. Inhibiting sGC may help reduce the excessive vasodilation associated with sepsis-induced vasoplegia. Methods This study utilized CADD to screen over 320 naturally occurring compounds from the PubChem database for potential sGC inhibitors. A comprehensive virtual screening process, which included protein-ligand docking, binding free energy calculations, and pharmacokinetic profiling, led to the identification of promising candidates such as Hypericin and Hypocrellin A2. Results These compounds demonstrated superior binding affinities and pharmacokinetic properties compared to existing inhibitors. Hypericin achieved a docking score of -14.232, indicating strong interactions with the receptor. It also exhibited favourable pharmacokinetic characteristics, including significant tissue-binding potential and stability within the binding pocket, as well as low predicted toxicity and a substantial safety margin. Conclusions This research lays the groundwork for future in vitro and in vivo studies, which could improve Hypericin-based effective therapies for sepsis-induced vasoplegia and hypotension.