Discovery of potent inhibitors of NS4B protein of dengue virus type 2 from natural compounds: an in silico approach
Tóm tắt
Introduction:
Dengue fever is an annual infectious epidemic disease caused by the Dengue virus, mainly found in tropical and subtropical regions. Of which, Dengue virus type 2 (DENV2) has been a major cause of severe cases globally. Currently, NS4B is one of the promising targets of dengue drug discovery, as it is crucial for the virus life cycle and highly conserved among different dengue strains. However, up till now, no potent synthetic DENV2 NS4B inhibitors have entered clinical research due to toxicity profiles. Therefore, this study aimed to search for new DENV2 NS4B inhibitors from in-house phytochemical compound database based on integration of in silico approaches.
Methods:
Initially, due to the lack of crystal structure of DENV2 NS4B protein, the 3D structure and binding site of this protein were predicted. Subsequently, virtual screening process was conducted through molecular docking and the most potential compounds in terms of binding affinity were selected for molecular dynamics simulations (MDs) and binding free energy calculation.
Results:
The flavonoid compound D155, derived from Valeriana hardwickii, and the saponin compound D170, extracted from Glinus oppositifolius, exhibited good binding affinities and bound well in the binding site of DENV2 NS4B protein. Notably, MDs study revealed that these two compounds formed stable interactions with NS4B protein during 200 ns of simulation and had a binding free energy <–20 kcal/mol.
Conclusions:
The findings suggested that D155 and D170 can be potential inhibitors targeting NS4B protein of DENV2. Further in vitro and in vivo studies are required to confirm their inhibitory activities.
