Structure-based discovery of dengue virus protease inhibitors.
Dengue virus belongs to the family Flaviviridae and is a major emerging pathogen for which the development of vaccines and antiviral therapy has seen little success. The NS3 viral protease is a potential target for antiviral drugs since it is required for virus replication. The goal of this study was to identify novel dengue virus (type 2; DEN2V) protease inhibitors for eventual development as effective anti-flaviviral drugs. The EUDOC docking program was used to computationally screen a small-molecule library for compounds that dock into the P1 pocket and the catalytic site of the DEN2V NS3 protease domain apo-structure [Murthy, K., Clum, S., Padmanabhan, R., 1999. Crystal structure and insights into interaction of the active site with substrates by molecular modeling and structural analysis of mutational effects. J. Biol. Chem. 274, 5573-5580] and the Bowman-Birk inhibitor-bound structure [Murthy, K., Judge, K., DeLucas, L., Padmanabhan, R., 2000. Crystal structure of dengue virus NS3 protease in complex with a Bowman-Birk inhibitor: implications for flaviviral polyprotein processing and drug design. J. Mol. Biol. 301, 759-767]. The top 20 computer-identified hits that demonstrated the most favorable scoring "energies" were selected for in vitro assessment of protease inhibition. Preliminary protease activity assays demonstrated that more than half of the tested compounds were soluble and exhibited in vitro inhibition of the DEN2V protease. Two of these compounds also inhibited viral replication in cell culture experiments, and thus are promising compounds for further development.
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, 77555, United States.
Suzanne M
SM
Tomlinson
Robert D
RD
Malmstrom
Andrew
A
Russo
Niklaus
N
Mueller
Yuan-Ping
YP
Pang
Stanley J
SJ
Watowich
D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D003716:Dengue Virus / Q000187:drug effects*; D015198:Designer Drugs / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D012995:Solubility; D000085242:Viral Proteases
D000998:Antiviral Agents; D015198:Designer Drugs; D011480:Protease Inhibitors; D012697:Serine Endopeptidases; C504449:NS3 protease, dengue virus; D000085242:Viral Proteases