Network Pharmacology Reveals the Potential of Dolastatin 16 as Diabetic Wound Healing Agent

Abstract

Dolastatin 16, a marine cyclic depsipeptide, was first isolated from the sea hare Dolabella Auricularia by Pettit et al. Since its bioactivity lacks of information, target identification is the indispensable strategy to reveal the potential target and mechanism of action of Dolastatin 16. Network pharmacology was utilized to identify the target associated with the disease, gene ontology, and KEGG pathway. The results demonstrated Matrix Metalloproteinase-9 (MMP9) as a potential target of Dolastatin 16 via network pharmacology analysis. The target was also mainly involved in TNF signaling pathway and foot ulceration-associated diabetic polyneuropathy. Further, the binding mode and dynamic behavior of the complex was investigated by molecular docking and molecular dynamics studies. In docking study, a native ligand (a hydroxamate inhibitor) and (R)-ND-336 were used as the ligand controls, demonstrating the binding energies of -6.6 and − 8.9 kcal/mol, respectively. The Dolastatin 16 complex showed the lowest binding energy of -9.7 kcal/mol, suggesting its higher potential as an inhibitor. Molecular dynamics also validated the stability of MMP9-Dolastatin complex throughout the simulation process. Dolastatin 16 may act as a MMP9 inhibitor and have potential to accelerate the wound healing process in diabetic foot condition.