In silico studies on Zika NS3 helicase: bedrock for antiviral drug design.

Abstract

Zika virus is a re-emerging infectious disease, which was declared to be a public health emergency of international concern due to its various reported complications ranging from microcephaly in newborn to Guillain-Barré Syndrome (GBS). Because less attention has been paid to this virus over time, literature has been lacking regarding the structural and conformational features of its proteins particularly the NS3 helicase protein. This dissertation has addressed two major aspects of Zika NS3 helicase protein: (i) the binding interactions and (ii) structural dynamics and conformational changes of the protein. Investigations were carried out on the various Zika NS3 helicase ligand binding landscapes using 10 ligands via molecular docking, of which the best 3 were subjected to molecular dynamic simulations and several post dynamics analyses. Ivermectin, HMC-HO1α and lapachol emerged as the best 3 ligands. The result of the analysis showed that the binding of Ivermectin to ssRNA site and Lapachol and HMC-HO1α to the ATPase site induces a more compact protein structure, thus stabilizing residue fluctuations. The pharmacophoric characteristics found in Lapachol, HMC-HO1α and Ivermectin may be utilized in the design of a potent hybrid drug that can show efficient inhibition of a multitude of diseases including the detrimental co-infection of ZIKV, Dengue and Chikungunya. Also in this study, a detailed structural dynamic analysis was carried out on the structural flexibility of the NS3 helicase protein after NITD008 binding via molecular dynamics simulation and other posts dynamic analysis including the Principal Component Analysis (PCA) and the Dynamic Cross Correlation (DCC) analysis. Result revealed a prominent shift in the P-Loop found at the ATP site of the helicase. This loop and helical flexible regions give new insight into the dynamic structural features of ZIKV NS3 Helicase. The PCA and DCC analysis result revealed a significant structural flexibility of the NITD008-NS3 Helicase system compared to the rigid unbound form of the protein. Furthermore, the NITD008-NS3 Helicase complex stability was also ensured via a 130ns molecular dynamic simulation, this has proven NITD008 as an effective potential inhibitor of the NS3 helicase protein. This research is of immense importance to the discovery of a potent Zika inhibitor and in medicine as it has proven potential inhibitors with a good binding affinity towards Zika NS3 helicase. Also, this study hopes to fill in the gap of information that has been missing regarding molecular studies on Zika virus to some extent.