[Optimization and identification of potential targets of obacunone against sepsis].

Objective: To investigate the molecular characteristics of obacunone, and to screen and identify potential targets of obacunone against sepsis.

Methods: The pharmacological parameters and molecular characteristics of obacunone were analyzed with the aid of the Traditional Chinese Medicine Systems Pharmacology Database Analysis Platform (TCMSP). The potential targets of obacunone against sepsis were screened using SwissTargetPrediction and Drug Repositioning and Adverse Drug Reaction Chemical-Protein Interactome (DRAR-CPI) software, with a Z'-score < -0.5. The anti-sepsis targets of obacunone were selected by Online Mendelian Inheritance in Man (OMIM), Comparative Toxicogenomics Database (CTD) and Therapeutic Target Database (TTD). The anti-sepsis potential target was identified by molecular docking software.

Results: The oral bioavailability of obacunone was 81.58% and the drug-likeness was 0.57 indicating that obacunone showed good drug formation. A total of 242 potential targets were screened through SwissTargetPrediction and DRAR-CPI software, 13 targets were directly related to sepsis. Cathepsin G (CTSG), caspase-1 (CASP1), S100 calcium binding protein A9 (S100A9), protein C (inactivator of coagulation factors V a and VIII a, PROC), mitogen-activated protein kinase 1 (MAPK1), glucose-6-phosphate dehydrogenase (G6PD), interleukin-10 (IL-10), migration inhibitory factor (MIF), complement C5a receptor 1 (C5AR1), caspase-3 (CASP3), CXC chemokine receptor 2 (CXCR2), thrombin receptor (F2R), nicotinamide phosphoribosyltransferase (NAMPT) were identified as the potential targets for anti-sepsis of obacunone by molecular docking software, the free binding energies were -32.55, 1.26, -30.00, 300.08, -31.88, -30.29, -21.38, -30.79, 16 777.84, -21.80, 6 443.36, -20.38, -23.47 kJ/mol, respectively.

Conclusions: Obacunone can inhibit blood coagulation and improve inflammatory response by regulating PROC and F2R. It regulates MIF, S100A9, G6PD and IL-10 to play a role in immune response. It regulates CTSG, CASP1, MAPK1, C5AR1 and CASP3 to protect sepsis-damaged organs. By regulating CXCR2, it can reduce the excessive migration of neutrophils to the site of inflammation, alleviate tissue damage. By regulating NAMPT, it improves cellular energy status, reduces oxidative stress, and protects cells from damage.