Identification of dengue viral RNA-dependent RNA polymerase inhibitor using computational fragment-based approaches and molecular dynamics study.
Dengue is a major public health concern in tropical and subtropical countries of the world. There are no specific drugs available to treat dengue. Even though several candidates targeted both viral and host proteins to overcome dengue infection, they have not yet entered into the later stages of clinical trials. In order to design a drug for dengue fever, newly emerged fragment-based drug designing technique was applied. RNA-dependent RNA polymerase, which is essential for dengue viral replication is chosen as a drug target for dengue drug discovery. A cascade of methods, fragment screening, fragment growing, and fragment linking revealed the compound [2-(4-carbamoylpiperidin-1-yl)-2-oxoethyl]8-(1,3-benzothiazol-2-yl)naphthalene-1-carboxylate as a potent dengue viral polymerase inhibitor. Both strain energy and binding free energy calculations predicted that this could be a better inhibitor than the existing ones. Molecular dynamics simulation studies showed that the dengue polymerase-lead complex is stable and their interactions are consistent throughout the simulation. The hydrogen-bonded interactions formed by the residues Arg792, Thr794, Ser796, and Asn405 are the primary contributors for the stability and the rigidity of the polymerase-lead complex. This might keep the polymerase in closed conformation and thus inhibits viral replication. Hence, this might be a promising lead molecule for dengue drug designing. Further optimization of this lead molecule would result in a potent drug for dengue.
a Department of Biotechnology , Indian Institute of Technology Madras , Chennai 600036 , Tamil Nadu , India.
Shanmugam
S
Anusuya
b Centre of Advanced Study in Crystallography and Biophysics , University of Madras , Guindy Campus, Chennai 600 025 , India.|c Bioinformatics Infrastructure Facility (BIF) , University of Madras , Guindy Campus, Chennai 600 025 , India.
Devadasan
D
Velmurugan
a Department of Biotechnology , Indian Institute of Technology Madras , Chennai 600036 , Tamil Nadu , India.
M Michael
MM
Gromiha
D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D020134:Catalytic Domain; D003716:Dengue Virus / Q000201:enzymology*; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors / Q000737:chemistry*
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D008024:Ligands; D012324:RNA-Dependent RNA Polymerase
RNA-dependent RNA polymerase; dengue; fragment growing; fragment library; fragment linking; fragment-based drug designing; lead molecule; molecular dynamics simulation; neighborhood search; substructure search