title: Structure-guided Discovery of a Novel Non-peptide Inhibitor of Dengue Virus NS2B-NS3 Protease.
abstract: Dengue fever is a fast emerging epidemic-prone viral disease caused by dengue virus serotypes 1-4. NS2B-NS3 protease of dengue virus is a validated target to develop antiviral agents. A major limitation in developing dengue virus protease inhibitors has been the lack of or poor cellular activity. In this work, we extracted and refined a pharmacophore model based on X-ray crystal structure and predicted binding patterns, followed by a three-dimensional flexible database filtration. These output molecules were screened according to a docking-based protocol, leading to the discovery of a compound with novel scaffold and good cell-based bioactivity that has potential to be further optimized. The discovery of this novel scaffold by combination of in silico methods suggests that structure-guided drug discovery can lead to the development of potent dengue virus protease inhibitors.
authors.affiliation: College of Pharmacy, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, 300071, China.|Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, 300071, China.
authors.forename: Linfeng
authors.initials: L
authors.lastname: Li
authors.affiliation: Duke-NUS Graduate Medical School, Program in Emerging Infectious Diseases, 8 College Road, Singapore, 169857, Singapore.
authors.forename: Chandrakala
authors.initials: C
authors.lastname: Basavannacharya
authors.affiliation: Duke-NUS Graduate Medical School, Program in Emerging Infectious Diseases, 8 College Road, Singapore, 169857, Singapore.
authors.forename: Kitti Wing Ki
authors.initials: KW
authors.lastname: Chan
authors.affiliation: College of Pharmacy, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, 300071, China.|Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, 300071, China.
authors.forename: Luqing
authors.initials: L
authors.lastname: Shang
authors.affiliation: Duke-NUS Graduate Medical School, Program in Emerging Infectious Diseases, 8 College Road, Singapore, 169857, Singapore.
authors.forename: Subhash G
authors.initials: SG
authors.lastname: Vasudevan
authors.affiliation: College of Pharmacy, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, 300071, China.|Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, 300071, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yin
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003198:Computer Simulation; D006224:Cricetinae; D018360:Crystallography, X-Ray; D003715:Dengue / Q000188:drug therapy / Q000821:virology; D003716:Dengue Virus / Q000187:drug effects* / Q000201:enzymology; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D062105:Molecular Docking Simulation / Q000379:methods; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D020365:RNA Helicases / Q000037:antagonists & inhibitors / Q000737:chemistry; D012697:Serine Endopeptidases / Q000737:chemistry; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D011480:Protease Inhibitors; D020365:RNA Helicases; D012697:Serine Endopeptidases; D017361:Viral Nonstructural Proteins; C080102:NS2B protein, flavivirus; C060028:NS3 protein, flavivirus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
keywords: dengue virus; dengue virus bioassay; pharmacophore; protease inhibitor; virtual screening