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Rational search for inhibitors of Dengue and Foot-and-Mouth Disease proteases

Grant number: 12/06633-2
Support Opportunities:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): June 01, 2012
Effective date (End): June 30, 2017
Field of knowledge:Physical Sciences and Mathematics - Chemistry - Organic Chemistry
Principal Investigator:Antonia Tavares Do Amaral
Grantee:Erika Piccirillo
Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated scholarship(s):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, BE.EP.DD


Discovery of bioactive compounds, initially, was done by trial and error, usually, through randomly tests of different natural products against various diseases. Nowadays, the design of bioactive compounds is based on the structure knowledge of the ligand (Ligand Based Drug Design - LBDD) and/or of the biological target (structure based drug design - SBDD, that includes Virtual Screening (VS) procedure). In the virtual screening, selection of potential ligands are done computationally (in silico) using virtual libraries with huge number of compounds.Dengue Fever and Foot-and-Mouth Disease (FMD) are viral infections, that occur in Brazil and abroad, causing significant socio-economic impact. At the same time, it has to be point out that antivirals design search is necessary when the vaccine is not available (e.g. for Dengue virus) or for an outbreak control (e.g. for FMD virus, pathogen infecting, exclusively, animals). In this PhD project we propose to apply some SBDD methodological approaches, specially Virtual Screening (VS) protocols to commercial molecules library in order to generate models to select potential inhibitors of viral proteases of Dengue Fever and of FMD. All procedures have been previously implemented in the group. These studies will be done from the 3D structures of Dengue and FMD proteases, respectively, NS2B/NS3 and Lbpro taken from PDB or obtained by homology model. In addition, enzymatic inhibition assays will be done in order to perform validation and optimization of the generated in silico models. All inhibition assays will be carried out by myself in collaboration with Prof. Dr. L. Juliano group from Department of Biophysics, UNIFESP-SP. The proteases used in this project will be provided from his group. Finally, from the Virtual Screening (VS) generated models we intend to be able to contribute to the understanding of ligand-receptor interactions, respectively in the Dengue NS2B/NS3 and FMD Lbpro systems. (AU)

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Scientific publications (5)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
PICCIRILLO, ERIKA; ALEGRIA, THIAGO G. P.; DISCOLA, KAREN F.; CUSSIOL, JOSE A. R. R.; DOMINGOS, RENATO M.; DE OLIVEIRA, MARCOS A.; DE REZENDE, LEANDRO; NETTO, LUIS E. S.; AMARAL, ANTONIA T-DO. Structural insights on the efficient catalysis of hydroperoxide reduction by Ohr: Crystallographic and molecular dynamics approaches. PLoS One, v. 13, n. 5, . (16/12392-9, 12/06633-2, 08/07971-3, 14/01614-5, 05/50056-6, 13/07937-8)
VIVIANI, LUCAS G.; PICCIRILLO, ERIKA; ULRICH, HENNING; AMARAL, ANTONIA T-DO. Virtual Screening Approach for the Identification of Hydroxamic Acids as Novel Human Ecto-5 `-Nucleotidase Inhibitors. JOURNAL OF CHEMICAL INFORMATION AND MODELING, v. 60, n. 2, p. 621-630, . (14/07248-0, 12/50880-4, 18/24678-0, 12/06633-2, 18/07366-4, 13/07937-8, 18/06381-0)
PICCIRILLO, ERIKA; MERGET, BENJAMIN; SOTRIFFER, CHRISTOPH A.; DO AMARAL, ANTONIA T.. Conformational flexibility of DENV NS2B/NS3pro: from the inhibitor effect to the serotype influence. Journal of Computer-Aided Molecular Design, v. 30, n. 3, p. 251-270, . (14/01614-5, 12/06633-2)
DANTAS, LUCAS S.; VIVIANI, LUCAS G.; INAGUE, ALEX; PICCIRILLO, ERIKA; REZENDE, LEANDRO DE; RONSEIN, GRAZIELLA E.; AUGUSTO, OHARA; MEDEIROS, MARISA H. G.; AMARAL, ANTONIA T. DO; MIYAMOTO, SAYURI. Lipid aldehyde hydrophobicity affects apo-SOD1 modification and aggregation. Free Radical Biology and Medicine, v. 156, p. 157-167, . (14/07248-0, 12/06633-2, 13/07937-8, 17/13804-1)
VIVIANI, LUCAS G.; PICCIRILLO, ERIKA; CHEFFER, ARQUIMEDES; DE REZENDE, LEANDRO; ULRICH, HENNING; CARMONA-RIBEIRO, ANA MARIA; T-DO AMARAL, ANTONIA. Be Aware of Aggregators in the Search for Potential Human ecto-5 `-Nucleotidase Inhibitors. Molecules, v. 23, n. 8, . (12/50880-4, 14/07248-0, 16/12392-9, 12/06633-2, 18/14871-7, 13/07937-8)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
PICCIRILLO, Erika. Virtual screening for protease inhibitors of dengue and foot-and-mouth disease virus: database building, molecular dynamics simulations and experimental validation. 2017. Doctoral Thesis - Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ) São Paulo.

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