Molecular dynamic simulation of complex NS2B-NS3 DENV2 protease with potential inhibitors of cyclic tripeptide

Abstract

The pathogenic dengue virus (DV) is a growing global threat for which there is no specific treatment and prevention. Several vaccines have been developed against the disease, but they only prevent the disease and reduce the risk of death. Consequently, the antiviral drug becomes the most powerful treatment to solve this problem. The virus possesses a two component NS2B-NS3 protease that cleaves viral precursor proteins, and therefore represents a target for the development of antiviral drugs. In many researches, several models of peptides inhibitor were generated in complexes with the NS2B-NS3 DENV2 protease by performing molecular docking. The goal of this research was to study the interaction of ligands as inhibitors for protein (enzyme) in solvent explicit condition by performing molecular dynamics simulation at 300 and 312 K. The simulations were performed on four disulfide cyclic tripeptide ligands (RGR, KRK, RRA and RKR) and two proline-proline based cyclic peptide ligands (RKK and KKR) compared with linear peptide inhibitor Bz-Nle-K-R-R-H as standard ligand. The results provide conformational changes of enzyme-inhibitor complex that is shown by root-meansquare deviation (RMSD) values. These results show that dynamic behavior of the complex occurs in the presence of solvent. The interaction between ligand and amino acid residue of enzyme changed during simulation. By these parameters, RKR becomes the best ligand compared with others. The ligand has hydrogen bond interaction with the residue of active side, and is stable during simulation at both temperatures. In conclusion, RKR ligand is proposed as an antiviral drug by performing molecular dynamics simulation.

Rational design of cyclic tetra and pentapeptides as therapeutic agents for dengue NS2B/NS3 protease using structure-based molecular docking (MOE and AutoDock 4.2)

“…The second criterion is the binding interactions of the peptide ligand with the dengue NS2B/NS3 catalytic triad (His51, Asp75, and Ser135), considered as qualitative results. Since the catalytic triad residues are signi icant for viral replication, therefore, by targeting at this site, it could wedge the viral replication (van Hell et al, 2009). For this reason, we have chosen the best conformation based on the interaction, including hydrogen bonding between ligand with minimum two interactions especially with the catalytic triad residues.…”

“…In comparison, there was little or no activity on the P2' and P4' roles (Li et al, 2005). The proposed of P1-P4 positions of the amino acids by Jun Li and co-workers have been used by Tambunan and Alamudi (Tambunan and Alamudi, 2010), (Usman et al, 2013) as well as by Sobia I., Usman A. Ashfaq (Idrees and Ashfaq, 2014) in the designing of cyclic peptide through disul ide linkage as dengue virus NS2B/NS3 protease inhibitor. The biological availability and metabolic stability challenges must be addressed when designing linear peptides as an inhibitor.…”

“…These problems were solved through the design and production of cyclic peptides with signi icant advantages of these peptides through a better permeability and good metabolic stability over linear peptides (Horton et al, 2002). Although the peptides have low stability, their high activity and speci icity make peptides are ideal for the design of drug inhibitors (ligands) and the cyclization of ligands by S-S disul ide bridge could improve their stability (van Hell et al, 2009).…”