Repurposing Anti-Dengue Compounds against Monkeypox Virus Targeting Core Cysteine Protease

Abstract

The monkeypox virus (MPXV) is an enveloped, double-stranded DNA virus belonging to the genus Orthopox viruses. In recent years, the virus has spread to countries where it was previously unknown, turning it into a worldwide emergency for public health. This study employs a structural-based drug design approach to identify potential inhibitors for the core cysteine proteinase of MPXV. During the simulations, the study identified two potential inhibitors, compound CHEMBL32926 and compound CHEMBL4861364, demonstrating strong binding affinities and drug-like properties. Their docking scores with the target protein were -10.7 and -10.9 kcal/mol, respectively. This study used ensemble-based protein-ligand docking to account for the binding site conformation variability. By examining how the identified inhibitors interact with the protein, this research sheds light on the workings of the inhibitors' mechanisms of action. Molecular dynamic simulations of protein-ligand complexes showed fluctuations from the initial docked pose, but they confirmed their binding throughout the simulation. The MMGBSA binding free energy calculations for CHEMBL32926 showed a binding free energy range of (-9.25 to -9.65) kcal/mol, while CHEMBL4861364 exhibited a range of (-41.66 to -31.47) kcal/mol. Later, analogues were searched for these compounds with 70% similarity criteria, and their IC₅₀ was predicted using pre-trained machine learning models. This resulted in identifying two similar compounds for each hit with comparable binding affinity for cysteine proteinase. This study's structure-based drug design approach provides a promising strategy for identifying new drugs for treating MPXV infections.

Keywords: cysteine proteinase; in silico methods; molecular docking; molecular dynamic simulations; monkeypox virus.

Figure 1

Three-dimensional representation of the predicted modeled structure of cysteine proteinase from MPXV, predicted using the AlphaFold program.

Figure 2

Quality assessment of the modeled structure: (a) Confidence scores of the residues of the modeled 3D structure of cysteine proteinase and (b) Quality assessment plot of the modeled 3D structure of cysteine proteinase. (RMSD is given in Å).

Figure 3

The middle structure of the three selected clusters with their corresponding binding pockets and binding site residues, (a,b) Cluster-1, (c,d) Cluster-2 and (e,f) Cluster-3.

Figure 4

The catalytic triad residues of MPXV core cysteine proteinase in the three structures selected from clustering (Cluster-1, Cluster-2, Cluster-3).

Figure 5

The 2D and 3D representations of the binding interactions of the complexes (a,d) Cluster-1 and CHEMBL4549312 (b,e) Cluster-2 and CHEMBL32926 (c,f) Cluster-3 and CHEMBL4861364. Compounds are illustrated in different colors.

Figure 6

The RMSD of the protein Cα-atoms and the ligand for the protein–ligand complex of (a,b) Cluster-2 and CHEMBL32926 and (c,d) Cluster-3 and CHEMBL4861364.

Figure 7

The 3D and 2D representations of the binding interactions of the Cluster-2 and CHEMBL32926 complex during the 100 ns MD simulation at the (a,c) 0 ns, (b,d) 5 ns, (e,g) 40 ns, and (f,h) 85 ns conformations.

Figure 8

The 3D and 2D representations of the binding interactions of the Cluster-3 and CHEMBL4861364 complex during the 100 ns MD simulation at the (a,c) 0 ns, (b,d) 10 ns, (e,g) 45 ns, and (f,h) 70 ns conformations.

Figure 9

The RMSF of the protein and the ligand for the protein–ligand complex of (a,b) Cluster-2 and CHEMBL32926 and (c,d) Cluster-3 and CHEMBL4861364.

Figure 10

Two similar compounds of CHEMBL32926 with a similarity threshold of 70% were searched in the ChemBL database.

Figure 11

Five similar compounds of CHEMBL4861364 with a similarity threshold of 70% searched in the ChemBL database.