Comparative molecular docking analysis for analyzing the inhibitory effect of Anakinra and Ustekinumab against IL17F

Interleukin 17 F is a member of IL-17 cytokine family with a 50% structural homology to IL-17A and plays a significant role either alone or in combination with IL-17A towards inflammation in Rheumatoid arthritis (RA). A growing number of drugs targeting IL-17 pathway are being tested against population specific disease markers. The major objective of this research was to investigate the anti-inflammatory effect of Anakinra (an IL-1 R1 inhibitor) and Ustekinumab (an IL-12 and IL-23 inhibitor) by targeting IL17F. The three dimensional structures of IL17F was taken from PDB while structures of drugs were taken from PubChem database. Docking was performed using MOE and Schrodinger ligand docking software and binding energies, including s-score using London-dG fitness function and glide score using glide internal energy function, between drug and targets were compared. Furthermore, Protein-Drug complex were subjected to 150 ns Molecular Dynamics (MD) Simulations using Schrodinger’s Desmond Module. Docking and MD simulation results suggest anakinra as a more potent IL17F inhibitor and forming a more structurally stable complex. Communicated by Ramaswamy H. Sarma</p

Panduratin A HOMO-LUMO map with energy gap.

BackgroundCurrently, there is no antiviral medication for dengue, a potentially fatal tropical infectious illness spread by two mosquito species, Aedes aegypti and Aedes albopictus. The RdRp protease of dengue virus is a potential therapeutic target. This study focused on the in silico drug discovery of RdRp protease inhibitors.MethodsTo assess the potential inhibitory activity of 29 phenolic acids from Theobroma cacao L. against DENV3-NS5 RdRp, a range of computational methods were employed. These included docking, drug-likeness analysis, ADMET prediction, density functional theory (DFT) calculations, and molecular dynamics (MD) simulations. The aim of these studies was to confirm the stability of the ligand-protein complex and the binding pose identified during the docking experiment.ResultsTwenty-one compounds were found to have possible inhibitory activities against DENV according to the docking data, and they had a binding affinity of ≥-37.417 kcal/mol for DENV3- enzyme as compared to the reference compound panduratin A. Additionally, the drug-likeness investigation produced four hit compounds that were subjected to ADMET screening to obtain the lead compound, catechin. Based on ELUMO, EHOMO, and band energy gap, the DFT calculations showed strong electronegetivity, favouravle global softness and chemical reactivity with considerable intra-molecular charge transfer between electron-donor to electron-acceptor groups for catechin. The MD simulation result also demonstrated favourable RMSD, RMSF, SASA and H-bonds in at the binding pocket of DENV3-NS5 RdRp for catechin as compared to panduratin A.ConclusionAccording to the present findings, catechin showed high binding affinity and sufficient drug-like properties with the appropriate ADMET profiles. Moreover, DFT and MD studies further supported the drug-like action of catechin as a potential therapeutic candidate. Therefore, further in vitro and in vivo research on cocoa and its phytochemical catechin should be taken into consideration to develop as a potential DENV inhibitor.</div

(A) Molecular electrostatic potential of catechin (B) Optimized structure of catechin.

(A) Molecular electrostatic potential of catechin (B) Optimized structure of catechin.</p

Showing DFT descriptors of the compound and control.

Showing DFT descriptors of the compound and control.</p

Docking poses for (a) Panduratin A and (b) Catechin in PDB: 6IZZ.

Docking poses for (a) Panduratin A and (b) Catechin in PDB: 6IZZ.</p

Solvent-accessible surface area (SASA) analysis of 6IZZ-panduratin A and 6IZZ-catechin complexes and apo-protein.

Solvent-accessible surface area (SASA) analysis of 6IZZ-panduratin A and 6IZZ-catechin complexes and apo-protein.</p

Molecular physicochemical descriptors and drug-likeness analysis of the selected compounds.

Molecular physicochemical descriptors and drug-likeness analysis of the selected compounds.</p

The Gibbs binding interactions decomposition diagram of (a) 6IZZ-panduratin A and (b) 6IZZ-catechin complexes based on (MM-GBSA).

The Gibbs binding interactions decomposition diagram of (a) 6IZZ-panduratin A and (b) 6IZZ-catechin complexes based on (MM-GBSA).</p

Number of Hydrogen bonds of (a) Panduratin A and (b) Catechin.

Number of Hydrogen bonds of (a) Panduratin A and (b) Catechin.</p

Showing properties of bonds of the compound and control.

Showing properties of bonds of the compound and control.</p