Structural, electronic characterization, and antiviral potential of a thiadiazol derivative targeting nucleoprotein of Lassa fever virus: insights from DFT investigation, pharmacokinetic, and molecular docking

Abstract

Lassa fever virus is amongst the most prevalent viral infections in the tropical regions of Africa, and it is an RNA virus that results in hemorrhage fever upon infection of its host. This study investigated the structural, electronic, and antiviral inhibitory potential of 1,2-bis(4-(benzo[c][1,2,5]thiadiazol-4-ylsulfonyl)piperazin-1-yl)ethane designated TBS via density functional theory (DFT) at the ωB97XD/6-311 + + G(2d,2d) level of theory. The results from this study showed the stability of the compound in the different optimizing phases, with relatively short bond lengths ranging between 1.4545 Å and 1.4573 Å for the contributing atoms in the general structure of the compound. Similarly, the HOMO–LUMO energy gap demonstrated a low reactivity due to the large difference between the HOMO and the LUMO (energy gap), which were 7.327 eV, 7.315 eV, 7.329 eV, and 7.327 eV for TBS_Choloroform, TBS_DSMO, TBS_Gas, and TBS_Water, respectively. The ADMET study provided significant evidence that the compound has the potential to be absorbed through the intestine, be partially distributed to the target, and have a high excretory index. Toxicity analysis revealed that the compound is not hepatotoxic, immunogenic, carcinogenic, mutagenic, or cytotoxic; however, it cannot be consumed orally because of 2 violations—MW > 500, NorO > 10—of the 5 Lipinski rules and 3 violations—MW > 480, WLOGP < -0.4, MR > 130, and #atoms > 50—of the Ghose rule. Molecular docking revealed that the ligand inhibitory/antiviral potential of the Lassa fever nucleoprotein was very high, as the interaction of the TBS ligand with 3MX5 resulted in a binding affinity of − 11.6 kcal/mol, and the interaction with 3MX2 resulted in a binding affinity of − 11.2 kcal/mol, which was better than that of the ribavirin reference drug (− 7.4 kcal/mol for both proteins). This result presents the TBS compound as a model for further experimental investigation of its antiviral inhibitory effects on Lassa fever virus (LFV).