Kanin Wichapong (MSc)
Kanin Whichapong (MSc)
Tel. ++49 345 55 25 043
e-mail: w_kanin(at)yahoo.com
Homology Modeling, Ligand Docking and 3D-QSAR Studies on Dengue and West-Nile-Virus Proteases
Project A: Docking and 3D QSAR on West-Nile-Virus Protease Inhibitors
West Nile Virus is becoming a widespread pathogen, infecting people on at least four continents with no effective treatment for these infections or many of their associated pathologies. A key enzyme that is essential for viral replication is the viral protease NS2BNS3, which is highly conserved among all flaviviruses. 3D-QSAR techniques, namely In the present study CoMFA (Comparative Molecular Field Analysis) and CoMSIA (Comparative Similarity Indicies Analysis), were applied to a set of 28 tetra-peptide inhibitors[1] of West Nile virus NS2B/NS3 protease. Several models, which are based on ligand-based alignment, automated alignment derived from molecular docking, as well as an alignment obtained by energy minimization of the ligands in the binding pocket, will be employed for comparison purpose. Information derived from the CoMFA and CoMSIA models will be helpful for the design and development of new potent, more drug-like inhibitors.
Project B: Molecular docking studies of Dengue NS2B/NS3 protease with its inhibitors
Dengue virus is a member of the Flaviviridae family which causes dengue fever and dengue hemorrhagic fever in millions of people each year in tropical and subtropical regions of the world. Currently, there is no vaccine or e.ective antiviral therapy for the four known serologically related virus types. The dengue virus genome contains a trypsin-like protease with a classical serine protease catalytic triad which constitutes part of the nonstructural protein 3 (NS3). The enzymatic activity of NS3 protease is enhanced by interactions with the NS2B protein, which acts as an essential cofactor. Therefore, dengue NS3 protease is an attractive therapeutic target for dengue virus infections. Homology models of Dengue NS2B/NS3 protease with its covalent bound peptidic inhibitor (Bz-Nle-Lys-Arg-Arg-H) were generated using the related West Nile NSB2B/NS3 Protease X-ray structure (2FP7) as template. The derived homology models were analyzed by means of molecular dynamics (MD) simulation. Known peptidic inhibitors[2-4] were docked to representative frames obtained from the MD simulations. The docking solutions of most compounds showed similar interactions at the different binding pockets P1-P3. The most potent inhibitors show in addition a hydrogen bond interaction to Tyr161 (NS3). These results together with the experimental Ki values indicated that Tyr161 at NS3 plays a significant role for inhibitor binding. The docking results of small non-peptidic inhibitors[4], which contain a basic guanidinyl group, showed that most compounds mainly interact with the P1-pocket, whereas interactions at the S2 and S3 pockets were not observed. The reduced interaction possibilities is possibly the reason for their high Ki values. The obtained results provide better understanding about the enzyme-ligand interactions and a guideline to assist the development of new potent inhibitors.
Publications
K. Wichapong, S. Pianwanit, W. Sippl, S. Kokpol
Homology Modeling and Molecular Dynamics Simulations of Dengue Virus NS2B/NS3 Protease: Insight into Molecular Interaction
J. Mol. Rec. 2009, submitted
Kanin Wichapong, Marc Lindner, Somsak Pianwanit, Sirirat Kokpol,
Wolfgang Sippl
Receptor-based 3D-QSAR studies of checkpoint Wee1 kinase inhibitors
European Journal of Medicinal Chemistry 2009, 44, 1383-1395
Poster Abstracts
K. Wichapong, S. Kokpol, W. Sippl
Virtual screening study of dengue virus NS2B/NS3 protease inhibitors
5th Summerschool on Drug Design
Vienna, 13. – 16.09.2009
K. Wichapong, S. Pianwanit, W. Sippl and S. Kokpol
Molecular Dynamics Simulation and Virtual Screening for Inhibitors of Dengue Virus NS2B/NS3 Protease
2009 ACS Meeting
Washington, USA, 16.-20.08.2009
K. Wichapong, S. Pianwanit, W. Sippl and S. Kokpol
Search for novel inhibitors of Dengue Virus NS2B/NS3 protease by combining virtual screening and MM-PBSA binding free energy calculation
eCheminfo 2008
Oxford, UK, 06.-08.05.2009
K. Wichapong, S. Kokpol, W. Sippl
Molecular docking studies of Dengue NS2B/NS3 protease with its inhibitors
3rd German Conference on Cheminformatics Goslar,
09.-11.11.2008
K. Wichapong, S. Kokpol, W. Sippl
Molecular docking studies of Dengue NS2B/NS3 protease with its inhibitors
International Conference on Drug Design and Discovery for Developing Countries
Trieste, Itay, 30.06.-04.07.2008
Kanin Wichapong, Somsak Pianwanit, Sirirat Kokpol and Wolfgang Sippl
3D-QSAR studies on tetra-peptide inhibitors of West Nile Virus NS2B/NS3 protease using CoMFA and CoMSIA
21. Darmstädter Modelling Workshop
Erlangen, 16.-17.05.2007.
Kanin Wichapong, Somsak Pianwanit, Sirirat Kokpol and Wolfgang Sippl
Molecular docking studies of Dengue NS2B/NS3 protease with its inhibitors
21. Darmstädter Modelling Workshop
Erlangen, 16.-17.05.2007.