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

Author(s)

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

Affiliation

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

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

• Document type: Journal article
• Source: Journal of Computer-Aided Molecular Design; v. 30, n. 3, p. 251-270, MAR 2016.
• Web of Science Citations: 8

Abstract

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)

• FAPESP's process: 14/01614-5 - Use of MD simulations to improve DENV NS2B/NS3 protease pharmacophore models, considering protease conformational flexibility, and to validate different serotype proteases homology models
• Grantee: Erika Piccirillo
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• FAPESP's process: 12/06633-2 - Rational search for inhibitors of Dengue and Foot-and-Mouth Disease proteases
• Grantee: Erika Piccirillo
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)