Drug Repurposing for Primary Lateral Sclerosis: A Molecular Dynamic Study

Abstract

Primary lateral sclerosis (PLS) is a neurodegenerative disorder of the adult motor system that controls voluntary muscles; characterised by a slowly progressive weakness and stiffness of leg upper motor neuron syndrome. Many effective drugs act by modulating multiple targets, Drug repositioning/Drug repurposing can be used as an alternative methodology for drug discovery, and this ‘poly-pharmacology’ can be a therapeutic requirement for complex diseases. This study focuses on repurposing of FDA approved drugs against Transactive response DNA binding protein of 43 kDa (TDP43) protein of PLS disease by molecular docking and dynamic studies. The ligands were chosen from the FDA-approved chemical list and the target receptor was retrived from protein data bank (PDB ID: 7Q8V). The molecular docking study was carried out using the AutoDock Vina program and the results were visualised through Discovery studio tool. The ADMET features of top 10 drugs were predicted using pkCSM online software. Molecular dynamic study was carried out by Desmond. Several drugs showed extremely high binding free energies for chosen target of TDP43 Protein. The results have led to the discovery of Indinavir, Adapalene, Alclometasone, Amsacrine and other FDA-approved drugs as potential candidates for the treatment of PLS. Molecular dynamic studies were carried out for the best two complexes, complex was found to be stable during molecular dynamic simulation. This study led to the identify of Indinavir and Amsacrine as potential candidates for the treatment of PLS. Hence these drugs can be evaluated further in animal model to establish drug for treating PLS.