Abstract
Monkeypox is a zoonotic contagious disease that has recently re-emerged in different countries worldwide. Due to the lack of an effective treatment that eliminates the virus, there is an urgent need to find effective drugs to stop the spread of the multi-country outbreak. The current study aimed to use computational methods to quickly identify potentially effective drugs against the Monkeypox virus (MPXV). Three MPXV proteins were targeted in this study due to their essential role in viral replication (a DNA-Dependent RNA Polymerase subunit (A6R)), a protein involved in cell entry (D8L), and a protein catalyzing the envelopment of intracellular mature virus particles (F13L). We virtually screened a library of 1615 FDA-approved compounds, utilizing different in-silico approaches including computational modeling, molecular docking, molecular dynamic (MD) simulation, and MM-GBSA. The compound Fludarabine was found to have the best docking score (-7.53 kcal/mol) in relation to the MPXV A6R protein. Additionally, Fludarabine showed in-silico activity on the D8L and F13L proteins. During the whole period of the 100 ns MD simulation, the complex of A6R and Fludarabine exhibited the best stability. This stability was reflected in a good score of MM-GBSA, with an average value of -44.62 kcal/mole in a range between -53.26 and -35.49 and a low value of standard deviation (3.76). Furthermore, Fludarabine blocked efficiently the Asn175 residue which has an important role in the attachment of the virus to a host cell. The results of this study recommend more in vitro studies on this compound, as a starting point to develop a novel treatment against MPXV.