title: Proteochemometrics analysis of substrate interactions with dengue virus NS3 proteases.
abstract: The prime side specificity of dengue protease substrates was investigated by use of proteochemometrics, a technology for drug target interaction analysis. A set of 48 internally quenched peptides were designed using statistical molecular design (SMD) and assayed with proteases of four subtypes of dengue virus (DEN-1-4) for Michaelis (K(m)) and cleavage rate constants (k(cat)). The data were subjected to proteochemometrics modeling, concomitantly modeling all peptides on all the four dengue proteases, which yielded highly predictive models for both activities. Detailed analysis of the models then showed that considerably differing physico-chemical properties of amino acids contribute independently to the K(m) and k(cat) activities. For k(cat), only P1' and P2' prime side residues were important, while for K(m) all four prime side residues, P1'-P4', were important. The models could be used to identify amino acids for each P' substrate position that are favorable for, respectively, high substrate affinity and cleavage rate.
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Box 591 BMC, SE751 24 Uppsala, Sweden.
authors.forename: Peteris
authors.initials: P
authors.lastname: Prusis
authors.forename: Maris
authors.initials: M
authors.lastname: Lapins
authors.forename: Sviatlana
authors.initials: S
authors.lastname: Yahorava
authors.forename: Ramona
authors.initials: R
authors.lastname: Petrovska
authors.forename: Pornwaratt
authors.initials: P
authors.lastname: Niyomrattanakit
authors.forename: Gerd
authors.initials: G
authors.lastname: Katzenmeier
authors.forename: Jarl E S
authors.initials: JE
authors.lastname: Wikberg
mesh_terms: D020650:Combinatorial Chemistry Techniques; D003716:Dengue Virus / Q000201:enzymology; D007700:Kinetics; D008954:Models, Biological; D011485:Protein Binding; D040901:Proteomics; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity; D000085242:Viral Proteases
chemical_list: D012697:Serine Endopeptidases; C504449:NS3 protease, dengue virus; D000085242:Viral Proteases