Use of MD simulations to improve DENV NS2B/NS3 protease pharmacophore models, considering protease conformational flexibility, and to validate different serotype proteases homology models

• Grant number: 14/01614-5
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: March 30, 2014
• End date: June 29, 2014
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal Investigator: Antonia Tavares Do Amaral
• Grantee: Erika Piccirillo
• Supervisor: Christoph A. Sotriffer
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Universität Würzburg, Germany
• Associated to the scholarship: 12/06633-2 - Rational search for inhibitors of Dengue and Foot-and-Mouth Disease proteases, BP.DD

Abstract

In order to seek novel NS2B/NS3 protease inhibitors and following the original PhD proposal, during the last year a VS protocols, composed of a sequence of different filters (pharmacophore, physical-chemical, similarity analyses, docking and visual inspection), were generated and were further applied to the ZINC database (~23x106 structures, release 12/2011). This VS model selected 47 (< 0.000002% of the original database) potential DENV NS2B/NS3 protease inhibitors. 10 compounds were purchased and tested against this protease, only 2 of which showed some activity against DENV-2 NS2B/NS3 protease.However, the NS2B conformational change, which seems to be important to protease activity, must be also considered in the VS model, leading, probably to a better model. Although important to understand and better describe the interaction between the NS2B region and the NS3 core, this aspect has not yet been explored.In this application, we propose to use, initially, Molecular Dynamic simulations to explore and gain more information about the interaction between the NS2B region and the NS3 core. Additionally, we intend to apply similar approach (Molecular Dynamic simulation) to generate pharmacophore models to other different serotypes, which use validated homology models. (AU)

Scientific publications

(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, MAY 21 2018. (16/12392-9, 12/06633-2, 08/07971-3, 14/01614-5, 05/50056-6, 13/07937-8)

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, MAR 2016. (14/01614-5, 12/06633-2)