Abstract
The COVID-19 era has prompted several researchers to search for a linkage between COVID-19 and its associated neurological manifestation. Toll-like receptor 4 (TLR-4) acts as one such connecting link. spike protein of SARS-CoV-2 can bind either to ACE-2 receptors or to TLR-4 receptors, leading to aggregation of α-synuclein and neurodegeneration via the activation of various cascades in neurons. Recently, dithymoquinone has been reported as a potent multi-targeting candidate against SARS-CoV-2. Thus, in the present study, dithymoquinone and its six analogues were explored to target 3CL
pro
(main protease of SARS-CoV-2), TLR4 and PREP (Prolyl Oligopeptidases) by using the molecular docking and dynamics approach. Dithymoquinone (DTQ) analogues were designed in order to investigate the effect of different chemical groups on its bioactivity. It is noteworthy to mention that attention was given to the feasibility of synthesizing these analogues by a simple photo-dimerisation reaction. The DTQ analogue containing the 4-fluoroaniline moiety [Compound (
4
)] was selected for further analysis by molecular dynamics after screening via docking-interaction analyses. A YASARA structure tool built on the AMBER14 force field was used to analyze the 100 ns trajectory by taking 400 snapshots after every 250 ps. Moreover, RMSD, RoG, potential energy plots were successfully obtained for each interaction. Molecular docking results indicated strong interaction of compound (
4
) with 3CL
pro
, TLR4 and PREP with a binding energy of −8.5 kcal/mol, −10.8 kcal/mol and −9.5 kcal/mol, respectively, which is better than other DTQ-analogues and control compounds. In addition, compound (
4
) did not violate Lipinski’s rule and showed no toxicity. Moreover, molecular dynamic analyses revealed that the complex of compound (
4
) with target proteins was stable during the 100 ns trajectory. Overall, the results predicted that compound (
4
) could be developed into a potent anti-COVID agent with the ability to mitigate neurological manifestations associated with COVID-19.