Paederia foetida is valued for its folk medicinal properties. This research aimed to assess the acute toxicity, hypoglycemic and anti-hemostasis properties of the methanolic extract of P. foetida leaves (PFLE). Acute toxicity of PFLE was performed on a mice model. Hypoglycemic and anti-hemostasis properties of PFLE were investigated on normal and streptozotocin-induced mice models. Deep learning, molecular docking, density functional theory, and molecular simulation techniques were employed to understand the underlying mechanisms through in silico study. Oral administration of PFLE at a dosage of 300 µg/kg body weight (BW) showed no signs of toxicity. Treatment with PFLE (300 µg/kg/BW) for 14 days resulted in a hypoglycemic condition and a 30.47% increase in body weight. Additionally, PFLE mixed with blood exhibited a 44.6% anti-hemostasis effect. Deep learning predicted the inhibitory concentration (pIC50, nM) of Cleomiscosins against SGLT2 and FXa to be 7.478 and 6.017, respectively. Molecular docking analysis revealed strong binding interactions of Cleomiscosins with crucial residues of the target proteins, exhibiting binding energies of -8.2 kcal/mol and -7.1 kcal/mol, respectively. ADME/Tox predictions indicated favorable pharmacokinetic properties of Cleomiscosins, and DFT calculations of frontier molecular orbitals analyzed the stability and reactivity of these compounds. Molecular simulation dynamics, principal component analysis and MM-PBSA calculation demonstrated the stable, compact, and rigid nature of the protein-ligand complexes. The methanolic PFLE exhibited significant hypoglycemic and anti-hemostasis properties. Cleomiscosin may have inhibitory properties for the development of novel drugs to manage diabetes and thrombophilia in the near future.
Keywords: Density-functional theory; Hemostasis; Hypoglycemia; Molecular docking; Molecular dynamics simulation; Paederia foetida.
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