title: Discovery of in silico hits targeting the nsP3 macro domain of chikungunya virus.
abstract: The recent emergence and re-emergence of alphaviruses, in particular the chikungunya virus (CHIKV), in numerous countries has invoked a worldwide threat to human health, while simultaneously generating an economic burden on affected countries. There are currently no vaccines or effective drugs available for the treatment of the CHIKV, and with few lead compounds reported, the vital medicinal chemistry is significantly more challenging. This study reports on the discovery of potential inhibitors for the nsP3 macro domain of CHIKV using molecular docking, virtual screening, and molecular dynamics simulations, as well as work done to evaluate and confirm the active site of nsP3. Virtual screening was carried out based on blind docking as well as focused docking, using the database of 1541 compounds from NCI Diversity Set II, to identify hit compounds for nsP3. The top hit compounds were further subjected to molecular dynamic simulations, yielding a greater understanding of the dynamic behavior of nsP3 and its complexes with various ligands, concurrently confirming the outcomes of docking, and establishing in silico lead compounds which target the CHIKV nsP3 enzyme.
authors.affiliation: School of Chemistry, University of Wollongong, Wollongong, 2522, Australia.
authors.forename: Phuong T V
authors.initials: PT
authors.lastname: Nguyen
authors.forename: Haibo
authors.initials: H
authors.lastname: Yu
authors.forename: Paul A
authors.initials: PA
authors.lastname: Keller
mesh_terms: D000246:Adenosine Diphosphate Ribose / Q000737:chemistry; D000998:Antiviral Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D020134:Catalytic Domain; D002646:Chikungunya virus / Q000187:drug effects / Q000201:enzymology*; D017076:Computer-Aided Design; D062313:Databases, Pharmaceutical; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004795:Enzyme Stability; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D015203:Reproducibility of Results; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; C089383:nsp3 protein, alphavirus; D000246:Adenosine Diphosphate Ribose
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