title: Allosteric pocket of the dengue virus (serotype 2) NS2B/NS3 protease: In silico ligand screening and molecular dynamics studies of inhibition.
abstract: The allosteric pocket of the Dengue virus (DENV2) NS2B/NS3 protease, which is proximal to its catalytic triad, represents a promising drug target (Othman et al., 2008). We have explored this binding site through large-scale virtual screening and molecular dynamics simulations followed by calculations of binding free energy. We propose two mechanisms for enzyme inhibition. A ligand may either destabilize electronic density or create steric effects relating to the catalytic triad residues NS3-HIS51, NS3-ASP75, and NS3-SER135. A ligand may also disrupt movement of the C-terminal of NS2B required for inter-conversion between the "open" and "closed" conformations. We found that chalcone and adenosine derivatives had the top potential for drug discovery hits, acting through both inhibitory mechanisms. Studying the molecular mechanisms of these compounds might be helpful in further investigations of the allosteric pocket and its potential for drug discovery.
authors.affiliation: Centre for Chemical Biology, Universiti Sains Malaysia, 11800 Penang, Malaysia. Electronic address: azatccb@gmail.com.
authors.forename: Azat
authors.initials: A
authors.lastname: Mukhametov
authors.affiliation: Advanced Studies in Genomics, Proteomics and Bioinformatics, University of Hawaii, 2565 McCarthy Mall, Honolulu, HI 96822, United States.
authors.forename: E Irene
authors.initials: EI
authors.lastname: Newhouse
authors.affiliation: Centre for Chemical Biology, Universiti Sains Malaysia, 11800 Penang, Malaysia.
authors.forename: Nurohaida Ab
authors.initials: NA
authors.lastname: Aziz
authors.affiliation: Centre for Chemical Biology, Universiti Sains Malaysia, 11800 Penang, Malaysia.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Saito
authors.affiliation: Centre for Chemical Biology, Universiti Sains Malaysia, 11800 Penang, Malaysia; Advanced Studies in Genomics, Proteomics and Bioinformatics, University of Hawaii, 2565 McCarthy Mall, Honolulu, HI 96822, United States; Department of Microbiology, University of Hawaii, 2538 McCarthy Mall, Honolulu, HI 96822, United States. Electronic address: alam@hawaii.edu.
authors.forename: Maqsudul
authors.initials: M
authors.lastname: Alam
mesh_terms: D000495:Allosteric Site; D003716:Dengue Virus / Q000187:drug effects / Q000201:enzymology*; D004353:Drug Evaluation, Preclinical; D006860:Hydrogen Bonding; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011480:Protease Inhibitors / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000378:metabolism*; D040681:Structural Homology, Protein; D013816:Thermodynamics; D000085242:Viral Proteases
chemical_list: D008024:Ligands; D011480:Protease Inhibitors; D012697:Serine Endopeptidases; C504449:NS3 protease, dengue virus; D000085242:Viral Proteases
keywords: Allosteric inhibitors; DENV2; Dengue; NS2B/NS3 protease