An In Silico Approach to Analyze Epicatechin Gallate and its Derivatives as Effective Antifibrotic Agents during Wound Healing

Abstract

The prospering wound healing treatment is one that minimizes the formation of connective tissue and reduces scar that is produced during healing process. Scar formation in healing can be reduced by blocking the prominent pathway responsible for it. Previous studies identify TGF-â as the major player in the pathways that lead to scar formation and thus can be targeted for exploring Antifibrotic drugs. The objective of the current study is to search and validate an effective inhibitor of TGF-â receptor to prevent scar formation during wound healing by utilizing the computational methods. Briefly, a group of newly discovered molecules from Drug Bank and other natural compounds predicted to act in TGF â pathway were selected to check their inhibitory activity against TGF-â1 receptor. The ligands were docked against the active site of TGF-âR1 in Autodock4. A natural compound, Epicatechin Gallate showed highest binding energy (-9.44 kcal/mol) compared to the control, SB505124 (-9.18 kcal/mol). Since previous studies have confirmed that Epicatechin Gallate is only effective in minor scars, design of an effective inhibitor for extensive scar was attempted by modifying the parent structure of Epicatechin Gallate. A series of ligands thus obtained exhibited better binding energy upon docking. Two such derived ligands showed a binding energy above -10.4kcal/mol. However, one of these derived ligands with added hydrophobicity at C5 position qualified for Drug likeness, Toxicity and ADME properties in PreADMET server. The same ligand also made a stable complex with the target as obtained in terms of RMSD and Total Energy measures by real time Molecular Dynamic Simulation studies. All the studies indicate S1 can act as effective inhibitor of TGF-â pathway. But further clinical trials were necessary to confirm its action.