Binding of Nucleotide Inhibitors to the NS5 RdRp of the ZIKA Virus in the Replication Initiation State

The bindings of several ribonucleoside triphosphate (NTP) inhibitors to the RNA-dependent RNA polymerase (RdRp) of the Zika virus (ZIKV) are studied herein to identify potential drug-like candidates that can inhibit the replication of the viral genome by RdRp.

In this study, a guanosine triphosphate (GTP) bound to RdRp structure is generated to model the replication initiation state of RdRp. Subsequently, the bindings of 30 NTP inhibitors to the GTP binding site of RdRp are studied in detail by using the molecular docking method. Based on the docking scores, four NTP inhibitors, such as 2'-Cmethyl- adenosine-5'-triphosphate (mATP), 7-deaza-2'-C-methyladenosine-TP (daza-- mATP), 1-N6-Ethenoadenosine-5'-triphosphate (eATP), and Remdesivir-5'-triphosphate (RTP) are shortlisted for further analysis by employing molecular dynamics simulations and binding free-energy methods.

These inhibitors are found to bind to RdRp quite strongly, as evident from their relative binding free energies that lie between -31.54 ± 4.54 to -89.46 ± 4.58 kcal/mol. Among these drugs, the binding of RTP to the GTP site of RdRp would generate the most stable complex, which would be about 45 kcal/mol more stable than the binding of GTP to RdRp.

Due to the highest stability of the RTP-RdRp complex, it is likely that RTP would inhibit the RdRp activities efficiently. However, due to the strong binding of other NTPs to RdRp, they may also inhibit RdRp activities. Nevertheless, experimental evaluations of the potency of these drugs against the ZIKV RdRp are required before their clinical use.