Targeting ebola virus VP40 protein through novel inhibitors: exploring the structural and dynamic perspectives on molecular landscapes

Ebola filovirus (EBOV) is one of the deadliest known infectious agents, and a cause of Western African epidemics from 2013 to 2016. The virus has infected nearly 3000 humans and almost 1900 have died. In the past few years, various small molecules have been discovered to display efficiency against EBOV and some of them have progressed towards clinical trials. Even though continuous attempts have been made to find antiEBOV therapeutics, no potential drugs are yet approved against this viral infection. The development of small antiviral inhibitors has gained tremendous attention in the attempt to overcome EVD. With this background, we seek to offer molecular insights into EBOV VP40 protein inhibition, using all atom molecular mechanics methodology and binding free energy calculations. We have selected five novel reported inhibitors against VP40 protein, namely Comp1, Comp2, Comp3, Comp4, and Comp5, and explored their binding against the same target. It was evident from the analysis that all the inhibitors displayed stability in complex with VP40 protein; however, Comp1 exhibited enhanced stability and compactness. Comp1 unveiled favorable binding, which accounted for positive correlation motions in the active site residues. Likewise, Comp1 revealed the most promising binding (Delta G(bind) - 40.3504 kcal/mol) as compared to the other four inhibitors, which disclosed relatively less favorable Delta G(bind). The highest binding energy of Comp1 to VP40 protein can be primarily endorsed to the upsurge in van der Waals energy by Delta E-vdW - 37.1609 kcal/mol and Coulomb energy by Delta E-ele - 52.7332 kcal/mol. Also, the hydrogen bond network is robust in Comp1-VP40 complex, with four hydrogen bonds, whilst it is less in other inhibitors. The outcomes from this report may assist in the advancement of novel VP40 inhibitors with high selectivity and potency for EVD therapeutics.

Automated summary

Ebola filovirus (EBOV) is one of the deadliest infectious agents known, causing epidemics in Western Africa from 2013 to 2016. Despite efforts to find anti-EBOV therapeutics, no approved drugs are available yet. This study focused on molecular insights into EBOV VP40 protein inhibition, identifying Comp1 as a potential highly selective and potent inhibitor for EVD therapeutics, with favorable binding interactions and stability.