In-silico screening of small compounds against Lassa fever haemorrhagic virus nucleoprotein

Abstract

Lassa fever hemorrhagic virus (LFHV) outbreaks in Nigeria continue to increase. With the possibility of a potentially deadly pandemic and the absence of a vaccine, an effective candidate drug that presents with no adverse effects and better clinical outcomes is urgently needed; hence, the aim of the study. Retrieved ligands: 5-(Methylene) evodiamine, N-(2-Fluorobenzoyl) evodiamine, N-[[2-(3-chlorophenyl)-5-(trifluoromethyl) pyrazol-3-yl]methyl]-2-(1-methyl-2,3-dihydroindol-5-yl) propanamide (NCTPMMDP), lauric acid, and sofosbuvir, and the target protein, 3MX5, were prepared and utilised for docking, molecular dynamics simulation, ADMET profiling, and DFT using standard protocols. The docking score for lauric acid was the lowest, with a value of - 6.1, followed by the standard drug and co-crystal control drug with scores of - 9.1 and - 8.9 kcal/mol, respectively. On the other hand, the scores of the other ligands ranged from - 9.5 to - 12.3 kcal/mol. Molecular simulations revealed fluctuations in the RMSD and RMSF values; however, overall, the formed complexes were stable during most of the docking simulation runs. Principal component analysis (PCA) analysis showed that all the ligands, apart from lauric acid, showed better conformational changes within the backbone of the protein. ADMET profiling showed that the ligands were better oral drug candidates than sofosbuvir, as revealed by their better absorption values and absolute compliance with the Lipinski rule of five. The DFT result showed that, apart from lauric acid, all the test ligands possess small energy gaps indicative of high reactivity. Put together, these findings indicate that the test ligands possess anti-LHFV potential that merits further in vivo and in vitro evaluations.

Keywords: DFT; Docking; Lassa fever virus; Nigeria; Nucleoprotein; Simulation.

Fig. 1

Visualisation outputs of the various ligands co-crystal to the target protein in 2D. Key: Figures A to F shows the 2 poses for the various ligands, while the unlabeled portion shows the various bond types.

Fig. 2

Visualisation outputs of the various ligands co-crystal to the target protein in 3D. Key: Figures A to F shows the 3D poses for the various ligands, while G and H show the various protein chains and ligand in the active site of the target protein.

Fig. 3

RMSD values of the various complexes.

Fig. 4

RMSF values of the formed complexes.

Fig. 5

A graphical illustration of the contacts (protein-ligand).

Fig. 6

Frequency of contacts made by the various amino acids during simulation.

Fig. 7

Ligand interaction properties (RMSD, rGyr, MolSA, SASA and PSA).

Fig. 8

PCA and eigenvalue rank plots for all the ligands. Key: Top right = control while for ligands 3893, 4,537,808, 49,804,500, 49,804,912 and 56,967,508, top left, middle left, middle right, bottom left and bottom right/.

Fig. 9

Dynamic cross-correlation matrix for the ligands. Key: Top right = control while for ligands 3893, 4,537,808, 49,804,500, 49,804,912 and 56,967,508, top left, middle left, middle right, bottom left and bottom right/.

Fig. 10

HUMO-LUMO energy analysis of the various ligands.