Conformational flexibility of DENV NS2B/NS3pro: from the inhibitor effect to the serotype influence

Autor(es)

Piccirillo, Erika ^[1] ; Merget, Benjamin ^[2] ; Sotriffer, Christoph A. ^[2] ; do Amaral, Antonia T. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Quim, Dept Quim Fundamental, Sao Paulo - Brazil

^[2] Univ Wurzburg, Inst Pharm & Lebensmittelchem, D-97070 Wurzburg - Germany

• Tipo de documento: Artigo Científico
• Fonte: Journal of Computer-Aided Molecular Design; v. 30, n. 3, p. 251-270, MAR 2016.
• Citações Web of Science: 8

Resumo

The dengue virus (DENV) has four well-known serotypes, namely DENV1 to DENV4, which together cause 50-100 million infections worldwide each year. DENV NS2B/NS3pro is a protease recognized as a valid target for DENV antiviral drug discovery. However, NS2B/NS3pro conformational flexibility, involving in particular the NS2B region, is not yet completely understood and, hence, a big challenge for any virtual screening (VS) campaign. Molecular dynamics (MD) simulations were performed in this study to explore the DENV3 NS2B/NS3pro binding-site flexibility and obtain guidelines for further VS studies. MD simulations were done with and without the Bz-nKRR-H inhibitor, showing that the NS2B region stays close to the NS3pro core even in the ligand-free structure. Binding-site conformational states obtained from the simulations were clustered and further analysed using GRID/PCA, identifying four conformations of potential importance for VS studies. A virtual screening applied to a set of 31 peptide-based DENV NS2B/NS3pro inhibitors, taken from literature, illustrated that selective alternative pharmacophore models can be constructed based on conformations derived from MD simulations. For the first time, the NS2B/NS3pro binding-site flexibility was evaluated for all DENV serotypes using homology models followed by MD simulations. Interestingly, the number of NS2B/NS3pro conformational states differed depending on the serotype. Binding-site differences could be identified that may be crucial to subsequent VS studies. (AU)

• Processo FAPESP: 14/01614-5 - Aplicação de dinâmica molecular para melhorar modelos farmacofóricos da protease NS2B/NS3 do DENV, considerando a flexibilidade conformacional da protease, e para validar modelos de homologia para diferentes serotipos de proteases
• Beneficiário: Erika Piccirillo
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado Direto
• Processo FAPESP: 12/06633-2 - Busca racional de inibidores de proteases virais da Dengue e da Febre Aftosa
• Beneficiário: Erika Piccirillo
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto