Rational search of ligands with inhibitory activity on the reproductive cycle of the dengue virus

• Grant number: 14/11476-9
• Support Opportunities: Regular Research Grants
• Start date: December 01, 2014
• End date: November 30, 2016
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Leo Degreve
• Grantee: Leo Degreve
• Host Institution: Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (FFCLRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Paulo Marcos Donate ; Victor Hugo Aquino Quintana

Abstract

Dengue, an infectious disease that has become a major threat to more than half the world's population, is caused by one of four serotypes of dengue virus. The multifunctional protein E of this virus operates, among other functions, merging with the host cell membrane which results in the formation of a channel by which the genetic material of the virus enters the cell in a key step for the virus replication by launching hand tools present in the cell. Thus inhibition of E protein activity can disrupt the reproductive cycle of the virus and thus can halt the disease. With the goal of identifying inhibitors , or blockers of the E protein , this project proposes a rational search for antiviral drugs capable of controlling the development of dengue in humans. This search will be done in stages involving different techniques. At first, computational methods will be used, among which the molecular simulation to investigate the structural properties of the protein and to identify the cavities where ligands can dock. In the second stage, substances that bind in these cavities with very attractive energies will be identified by techniques like "docking" that are well established. These substances will be synthesized in the third step and, in the fourth step, their inhibitory activities on the dengue virus cycle will be evaluated. These studies will be complemented by quantum approach to understand the insertion procedures of the ligands in the protein cavities. The results will provide the identification of substances with effective antiviral activity against the development of dengue virus with clinical applications. (AU)