An Exploration of the Inhibitory Mechanism of Rationally Screened Benzofuran-1,3,4-Oxadiazoles and-1,2,4-Triazoles as Inhibitors of NS5B RdRp Hepatitis C Virus through Pharmacoinformatic Approaches

Abstract

Benzofuran, 1,3,4-oxadiazole, and 1,2,4-triazole are privileged heterocyclic moieties that display the most promising and wide spectrum of biological activities against a wide variety of diseases. In the current study, benzofuran-1,3,4-oxadiazole BF1-BF7 and benzofuran-1,2,4-triazole compounds BF8-BF15 were tested against HCV NS5B RNA-dependent RNA polymerase (RdRp) utilizing structure-based screening via a computer-aided drug design (CADD) approach. A molecular docking approach was applied to evaluate the binding potential of benzofuran-appended 1,3,4-oxadiazole and 1,2,4-triazole BF1-BF15 molecules. Benzofuran-1,3,4-oxadiazole scaffolds BF1-BF7 showed lesser binding affinities (-12.63 to -14.04 Kcal/mol) than benzofuran-1,2,4-triazole scaffolds BF8-BF15 (-14.11 to -16.09 Kcal/mol) against the HCV NS5B enzyme. Molecular docking studies revealed the excellent binding affinity scores exhibited by benzofuran-1,2,4-triazole structural motifs BF-9 (-16.09 Kcal/mol), BF-12 (-15.75 Kcal/mol), and BF-13 (-15.82 Kcal/mol), respectively, which were comparatively better than benzofuran-based HCV NS5B inhibitors' standard reference drug Nesbuvir (-15.42 Kcal/mol). A molecular dynamics simulation assay was also conducted to obtain valuable insights about the enzyme-compounds interaction profile and structural stability, which indicated the strong intermolecular energies of the BF-9+NS5B complex and the BF-12+NS5B complex as per the MM-PBSA method, while the BF-12+NS5B complex was the most stable system as per the MM-GBSA calculation. The drug-likeness and ADMET studies of all the benzofuran-1,2,4-triazole derivatives BF8-BF15 revealed that these compounds possessed good medicinal chemistry profiles in agreement with all the evaluated parameters for being drugs. The molecular docking affinity scores, MM-PBSA/MM-GBSA and MD-simulation stability analysis, drug-likeness profiling, and ADMET study assessment indicated that N-4-fluorophenyl-S-linked benzofuran-1,2,4-triazole BF-12 could be a future promising anti-HCV NS5B RdRp inhibitor therapeutic drug candidate that has a structural agreement with the Nesbuvir standard reference drug.

Keywords: ADMET studies; DFT studies; MD simulations; MM-PBSA; RdRp NS5B inhibitors; SAR; benzofuran derivatives; energy decomposition analysis; hepatitis C; molecular docking.

Figure 1

Structure of the HCV NS5B RNA-dependent RNA polymerase (PDB ID-4TLR) and the main allosteric regions for allosteric drug discovery.

Figure 2

HCV NS5B Palm Site-II pocket allosteric residues with Nesbuvir inhibitor (PDB ID-4TLR).

Figure 3

Allosteric inhibitors previously reported in the literature targeting different allosteric regions of the NS5B polymerase of HCV [26,27,28,29,30,31,32].

Figure 4

Workflow of anti-HCV NS5B inhibitors drug discovery via CADD approach.

Figure 5

The binding conformation of BF-9 in 3D (upper panel) and 2D (lower panel) with the HCV NS5B PS-II allosteric site.

Figure 6

The binding conformation of BF12 in 3D (upper panel) and 2D (lower panel) with the HCV NS5B PS-II allosteric site.

Figure 7

The binding conformation of BF13 in 3D (upper panel) and 2D (lower panel) with the HCV NS5B PS-II allosteric site.

Figure 8

SAR of benzofuran-1,2,4-triazole BF-9, BF-12, and BF-14 hybrid structures.

Figure 9

Analysis based on molecular dynamics simulation. (A) RMSD, (B) RMSF, (C) intermolecular hydrogen bonds analysis.

Figure 10

Molecular orbital orientations of compounds BF-9, BF-12, and BF-13 at LanL2DZ/B3LYP DFT levels in the ground state.