Novel guanosine derivatives against Zika virus polymerase in silico

Abstract

The Zika virus (ZIKV) outbreak, which started in the year 2015, is considered the fastest and most widely spread outbreak reported for this flavivirus. The polymerase domain of the NS5 protein has been targeted in other viral infections and is recognized as a suitable target in ZIKV infection. Different novel modified compounds against ZIKV NS5 have been tested in silico. A few structures have been solved for ZIKV polymerase and deposited in the protein data bank website. Two of these solved structures (with a resolution of less than 1.9 A) are used in this study to test the binding of 74 novel compounds in silico. Molecular docking is used to quantify the binding affinities of ZIKV polymerase and compare it to the hepatitis C virus NS5B. A total of 19 novel compounds revealed results that are either similar to or better than the physiological molecule, guanosine triphosphate. Water molecules are found to facilitate the binding of the compounds to ZIKV RNA-dependent RNA polymerase (RdRp) structures. The presented 19 novel compounds represent good binders to ZIKV RdRp and could be suitable candidates for developing a new and effective anti-ZIKV polymerase nucleotide inhibitor.

Keywords: NS5; RNA-dependent RNA polymerase; Zika virus; drug-protein interaction; guanosine derivatives; molecular docking.

Figure 1

The docking scores calculated by AutoDock Vina software for three groups of modifications to GTP, group I (A), group II (B), and group III (C). The docking study was performed using two ZIKV RdRp solved structures (PDB ID: 5WZ3 and 5U04), and one HCV RdRp solved structure (PDB ID: 2XI3) for comparison. The average values of the docking scores for ZIKV RdRp are represented by the orange line while HCV RdRp docking values in blue lines. GTP, guanosine triphosphate; HCV, hepatitis C virus; RdRp, RNA‐dependent RNA polymerase; ZIKV, Zika virus

Figure 2

The docking complexes of GTP to ZIKV NS5 RdRp (PDB ID: 5WZ3 (A) and 5U04 (B)). ZIKV RdRp is represented by the colored cartoon while the amino acids involved in the interactions are represented by lines and labeled by their three‐letter code. GTP is represented according to the atom type in stick color ; C, green; H, white; O, red; N, blue; P, orange. Water is represented bye red spheres while yellow dashed lines represente the polar contact. GTP, guanosine triphosphate; NS5, non‐structural 5; RdRp, RNA‐dependent RNA polymerase; ZIKV, Zika virus