Fosamprenavir and Tirofiban to combat COPD and cancer: A drug repurposing strategy integrating virtual screening, MD simulation, and DFT studies

Abstract

Matrix metalloproteinases (MMPs) are involved in different pathophysiological conditions like cancer, COPD, asthma, and inflammatory diseases. Among these MMPs, macrophage metalloelastase is one of the prime targets for COPD, and cancer. Therefore, to combat such diseases, potent novel macrophage metalloelastase inhibitors can be considered. Here, the classification-based molecular modeling was performed on large data of macrophage metalloelastase inhibitors that identified dibenzofuran, and diphenyl ether groups as important substructures contributing towards potent macrophage metalloelastase inhibition. This information was further implicated in repurposing marketed drugs through fragment-based and molecular docking-based virtual screening with molecular dynamics (MD) simulation-based stability validation and DFT calculations. This study identified fosamprenavir and tirofiban as promising hits that can exhibit potent macrophage metalloelastase inhibition which was also validated by the MD simulation and DFT-based calculations. Therefore, this study not only revealed these repurposed drugs as effective macrophage metalloelastase inhibitors but also opened up a horizon in developing novel potent macrophage metalloelastase inhibitors for the management of cancer and COPD in the future.