Murali Aarthy and Sanjeev Kumar Singh* Pages 1585 - 1602 ( 18 )
Background: Dengue fever, a major public health problem in the tropical and sub-tropical countries caused by the infection of Dengue virus transmitted by the anthropod vectors. The dengue virus infection is represented as the “Neglected Tropical Diseases” by the world health organization. The structural protein E binds to the receptor on the host cell surface during infection and the binding directs to the endocytic pathway. The conformational change of the envelope protein helps to infuse the viral lipid membrane and delivers the viral genome into the cytosol. No specific treatments are available till date and development of the vaccine for the DENV is challenging due to the immunization and longlasting protection against all four serotypes. Hence, identification of potent inhibitors would overlay the therapeutics against the mediated diseases.
Objective: Our study focuses on developing the novel potent inhibitors to inhibit the viral attachment and membrane fusion of the Dengue virus Envelope protein.
Methods: The crystal structure of Dengue Envelope protein has been retrieved from the protein data bank and optimized through Schrödinger. The structure-based virtual screening based on the cocrystallised ligand has been carried out with the small molecule libraries, and based on the docking score, interaction and energy value best complexes were selected. The selected complexes were further taken forward for the conformational stability analysis through Molecular dynamics simulation.
Results: Around 55 molecules from the three databases were identified as potential binders to the envelope protein and the docking studies revealed that the top compounds possess strong interaction with the good energies. The Molecular electrostatic surface potential of the top five compounds states that the interactions were observed mostly in the electropositive region. Finally, the best 5 compounds carried further for molecular dynamics simulations exposed that they were highly stable and no loss of interactions was observed between those complexes.
Conclusion: Hence, from the results, it is evident that the compounds DB00179, Quercetin, Silymarin, Dapagliflozlin and Fisetin could be novel and potent candidates to inhibit the DENV envelope protein.
Dengue virus, Envelope protein, Structure-based screening, Small molecule inhibitors, Molecular dynamics simulation.
Department of Bioinformatics, Computer Aided Drug Design and Molecular Modelling Lab, Alagappa University, Karaikudi- 630004, Tamil Nadu, Department of Bioinformatics, Computer Aided Drug Design and Molecular Modelling Lab, Alagappa University, Karaikudi- 630004, Tamil Nadu