Quercetin derivatives as non-nucleoside inhibitors for dengue polymerase: molecular docking, molecular dynamics simulation, and binding free energy calculation.
Dengue is an important public health problem in tropical and subtropical regions of the world. Neither vaccine nor an antiviral medication is available to treat dengue. This insists the need of drug discovery for dengue. In order to find a potent lead molecule, RNA-dependent RNA polymerase which is essential for dengue viral replication is chosen as a drug target. As Quercetin showed antiviral activity against several viruses, quercetin derivatives developed by combinatorial library synthesis and mined from PubChem databases were screened for a potent anti-dengue viral agent. Our study predicted Quercetin 3-(6″-(E)-p-coumaroylsophoroside)-7-rhamnoside as a dengue polymerase inhibitor. The results were validated by molecular dynamics simulation studies which reveal water bridges and hydrogen bonds as major contributors for the stability of the polymerase-lead complex. Interactions formed by this compound with residues Trp795, Arg792 and Glu351 are found to be essential for the stability of the polymerase-lead complex. Our study demonstrates Quercetin 3-(6″-(E)-p-coumaroylsophoroside)-7-rhamnoside as a potent non-nucleoside inhibitor for dengue polymerase.
a Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences , Indian Institute of Technology Madras , Chennai 600036 , Tamilnadu , India.
Shanmugam
S
Anusuya
a Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences , Indian Institute of Technology Madras , Chennai 600036 , Tamilnadu , India.
M Michael
MM
Gromiha
D000998:Antiviral Agents / Q000494:pharmacology*; D001665:Binding Sites / Q000502:physiology; D003715:Dengue / Q000188:drug therapy*; D003716:Dengue Virus / Q000187:drug effects*; D055808:Drug Discovery / Q000379:methods; D019277:Entropy; D006801:Humans; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation / Q000379:methods; D056004:Molecular Dynamics Simulation; D011794:Quercetin / Q000494:pharmacology*; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D011794:Quercetin; D012324:RNA-Dependent RNA Polymerase
RNA-dependent RNA polymerase; binding free energy; dengue; flavonoids; molecular dynamics simulation; non-nucleoside inhibitor; quercetin