title: Exploring the binding of peptidic West Nile virus NS2B-NS3 protease inhibitors by NMR.
abstract: West Nile virus (WNV) NS2B-NS3 protease is an important drug target since it is an essential protein for the replication of the virus. In order to determine the minimum pharmacophore for protease inhibition, a series of dipeptide aldehydes were synthesized. The 50% inhibitory concentration (IC(50)) measurements revealed that a simple acetyl-KR-aldehyde was only threefold less active than 4-phenyl-phenylacetyl-KKR-aldehyde (1) (Stoermer et al., 2008) that was used as the reference compound. The ligand efficiency of 0.40 kcal/mol/HA (HA=heavy atom) for acetyl-KR-aldehyde is much improved compared to the reference compound 1 (0.23 kcal/mol/HA). The binding of the inhibitors was examined using (1)H-(15)N-HSQC experiments and differential chemical shifts were used to map the ligand binding sites. The biophysical studies show that the conformational mobility of WNV protease has a major impact on the design of novel inhibitors, since the protein conformation changes profoundly depending on the structure of the bound ligand.
authors.affiliation: Experimental Therapeutics Center, Nanos, Singapore, Singapore.
authors.forename: CongBao
authors.initials: C
authors.lastname: Kang
authors.forename: Shovanlal
authors.initials: S
authors.lastname: Gayen
authors.forename: Weiling
authors.initials: W
authors.lastname: Wang
authors.forename: Rene
authors.initials: R
authors.lastname: Severin
authors.forename: Angela Shuyi
authors.initials: AS
authors.lastname: Chen
authors.forename: Huichang Annie
authors.initials: HA
authors.lastname: Lim
authors.forename: Cheng San Brian
authors.initials: CS
authors.lastname: Chia
authors.forename: Andreas
authors.initials: A
authors.lastname: Schüller
authors.forename: Danny Ngoc Phouc
authors.initials: DN
authors.lastname: Doan
authors.forename: Anders
authors.initials: A
authors.lastname: Poulsen
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Hill
authors.forename: Subhash G
authors.initials: SG
authors.lastname: Vasudevan
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Keller
mesh_terms: D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D011480:Protease Inhibitors / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D020365:RNA Helicases / Q000737:chemistry / Q000378:metabolism; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000378:metabolism*; D014902:West Nile virus / Q000201:enzymology*; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: 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