Drug Designing: Open Access
Open Access

Screening for novel anti-dengue virus NS3/NS2B inhibitor

International Conference and Exhibition on Computer Aided Drug Design & QSAR

October 29-31, 2012 DoubleTree by Hilton Chicago-North Shore, USA

Norihito Kawashita, Sabar Pambudi, Rie Kashiwada1, Teruo Yasunaga, Kazuyoshi Ikuta, Takeshi Kurosu and Tatsuya Takagi

Scientific Tracks Abstracts: Drug Design

Abstract :

Dengue virus (DENV) infection causes an epidemic in tropical region and often causes a potentially lethal complication called dengue hemorrhagic fever. Unfortunately, there are no effective drugs and vaccines against this infection; it is important subject to develop them. DENV non-structural protein (NS) 3, which is viral protease, is a potential target for therapy. Under this background, we carried out search of novel DENV protease inhibitors by in silico screening. We obtained crystal structure of dengue virus NS2B/NS3 protease complex (2FOM.pdb). NS2B is the cofactor of NS3 protease and it is essential for protease activity. Therefore, NS3 protease has two target cavities: substitute binding region and NS2B binding region. Now we targeted NS2B binding region and carried out in silico screening. The screened database was MOE leadlike database which contains about 780,000 compounds. All of these calculations were operated by MOE (CCG Inc.). From the screening result, we selected the top 100 compounds in the docking score and then purchased 39 compounds. To examine the inhibitory activity of compounds in viral replication, thirty nine candidates were screened by focus-reduction assay using DENV-2 New Guinea C strain. In the result, compound A showed EC 50 =7.95μM and slightly weal cell toxicity compared with ARDP006, known protease inhibitor of DENV. From the binding mode analysis, this compound had interaction with Lys20 and Met59 in NS2B binding site. Now we try to modify the compound and to search the different kinds of compounds by in silico method.

Biography :

Norihito Kawashita has completed his Ph.D on 2005 from Osaka University and then he moved to Research Institute for Microbial Diseases, Osaka University for designated research associate and assistant professor. He has been assistant professor of Graduate School of Pharmaceutical Sciences, Osaka University since 2007. His research topics are antiviral drug design and development, prediction of drug resistance, and analysis of organic reaction mechanism by computational chemistry.