Identification of potential inhibitors of Zika virus NS5 RNA-dependent RNA polymerase through virtual screening and molecular dynamic simulations

Abstract

Zika virus (ZIKV) is one of the mosquito borne flavivirus with several outbreaks in past few years in tropical and subtropical regions. The non-structural proteins of flaviviruses are suitable active targets for inhibitory drugs due to their role in pathogenicity. In ZIKV, the non-structural protein 5 (NS5) RNA-Dependent RNA polymerase replicates its genome. Here we have performed virtual screening to identify suitable ligands that can potentially halt the ZIKV NS5 RNA dependent RNA polymerase (RdRp). During this process, we searched and screened a library of ligands against ZIKV NS5 RdRp. The selected ligands with significant binding energy and ligand-receptor interactions were further processed. Among the selected docked conformations, top five was further optimized at atomic level using molecular dynamic simulations followed by binding free energy calculations. The interactions of ligands with the target structure of ZIKV RdRp revealed that they form strong bonds within the active sites of the receptor molecule. The efficacy of these drugs against ZIKV can be further analyzed through in-vitro and in-vivo studies.

Keywords: Binding free energy; Docking studies; Molecular dynamics; NS5 RNA-dependent RNA polymerase; Virtual screening; Zika virus.

Fig. 1

Flow chart showing virtual screening process for Zika virus polymerase (PDB ID 5WZ3).

Fig. 2

Protein structure of Zika virus NS5 protein (PDB ID 5WZ3) in complex with docked compounds (sticks) at the active site pocket as shown in (A) Cartoon presentation and (B) Surface view.

Fig. 3

(A) 2D representation of interaction between MMs02998601 and target residues of ZIKV NS5 polymerase. (B) 2D representation of interaction between MMs02899945 and target residues of ZIKV NS5 polymerase. (C) 2D representation of interaction between MMs02321984 and target residues of ZIKV NS5 polymerase. (D) 2D representation of interaction between MMs02517431 and target residues of ZIKV NS5 polymerase. (E) 2D representation of interaction between MMs02374310 and target residues of ZIKV NS5 polymerase. (F) 2D representation of interaction between MMs03915724 and target residues of ZIKV NS5 polymerase. (G) 2D representation of interaction between MMs00951683 and target residues of ZIKV NS5 polymerase. (H) 2D representation of interaction between 56949972 (PubChem) and target residues of ZIKV NS5 polymerase. (I) 2D representation of interaction between MMs02329489 and target residues of ZIKV NS5 polymerase. (J) 2D representation of interaction between ZINC000082155264 and target residues of Zika NS5 Polymerase.

Fig. 4

RMSDs of backbone atoms (C, Cα, N) for protein of each docked complex with respect to time. Color key: brown MMs02998601, red MMs02899945, green MMs02321984, blue MMs02517431 and yellow MMs02374310.