Computational predictions of artificial nucleoside triphosphates as potent inhibitors of RNA-dependent RNA polymerase of the ZIKA virus

As the RNA-dependent RNA polymerase (RdRp) of the Zika virus (ZIKV) is responsible for replicating the viral RNA genome inside host cells, its inhibition is necessary to control the Zika viral disease. Here, the interactions of 16 artificial RNA and DNA nucleoside triphosphates with the substrate active site of RdRp are studied in detail by using the molecular docking technique. The top 8 hits containing ligands such as ZTP, BTP, STP, XTP, dZTP, dBTP, dSTP, and dXTP were further studied by using molecular dynamics, and MM/GBSA Freeenergy methods. It is revealed that among various nucleoside triphosphates studied herein, the dBTP would bind to RdRP most strongly with a binding free energy (Delta Gbind) of -70.40 +/- 4.6 kcal/mol followed by dZTP with a Delta Gbind of -67.37 +/- 3.1 kcal/mol. The binding of these artificial nucleoside triphosphates to RdRp is about 22-26 kcal/mol more stable than that of the natural nucleoside triphosphate GTP. Therefore, it is expected that dBTP and dZTP would inhibit the activities of RdRp strongly. The molecular mechanisms of inhibition of RdRp activities are also discussed and compared with experimental studies.