Density functional theory and molecular dynamics simulation support Ganoderma lucidum triterpenoids as broad range antagonist of matrix metalloproteinases

Abstract Matrix metalloproteinases (MMPs) actively caused enzymatic proteolysis of extracellular matrix (ECM) and cell surface proteins, suggested as critical for connective tissue that results in progressive aging and other diseases. Numerous efforts have been conducted to design the broad-range of synthetic inhibitors for MMPs but none of them have successfully passed the clinical trials. Recently, Ganoderma lucidum triterpenoids were reported with significant medicinal beneficial effects including free radical-scavengers and anti-cancer activity. However, their concealed property as antagonist of MMPs is not yet explored. Hence, this study attempts to elucidate the Ganoderma lucidum triterpenoids potential as broad range of MMPs inhibitor using computational chemistry approaches. Herein, 100 Ganoderma lucidum triterpenoids were virtually screened against the model MMPs, i.e. gelatinase (MMP2), stromelysin (MMP3), collagenase (MMP8) and metalloelastase (MMP12) followed by ADME profiling, and results into prediction of 14 bioactive triterpenoids as broad spectrum MMPs inhibitors. Furthermore, stringent extra precision molecular docking by Glide protocol revealed Ganoderiol D and Ganodermanotriol as potential antagonist of model MMPs. These triterpenoids were further studied by density functional methods and in docked complexes of MMPs using molecular dynamics simulation, predicted the non-reactivity of triterpenoids and established the MMPs-triterpenoids complex stability by strong intermolecular interactions (hydrogen bonds, hydrophobic and polar interactions), respectively. Furthermore, binding free energy calculations deduced the significant involvement of coulomb and van der Waals forces in the respective MMP-triterpenoid complexes stability, supported the Ganoderiol D and Ganodermanotriol as broad range antagonist of MMPs.