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In silico identification of novel competitive and alosteric inhibitors of falcipains 2 and 3

Grant number: 16/24587-9
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): March 01, 2017
Effective date (End): November 30, 2019
Field of knowledge:Biological Sciences - Biophysics - Molecular Biophysics
Principal Investigator:Vitor Barbanti Pereira Leite
Grantee:Jorge Enrique Hernández González
Host Institution: Instituto de Biociências, Letras e Ciências Exatas (IBILCE). Universidade Estadual Paulista (UNESP). Campus de São José do Rio Preto. São José do Rio Preto , SP, Brazil
Associated scholarship(s):18/24205-4 - Probing in silico the allosteric inhibition of falcipain 2 as an approach for designing new antimalarials, BE.EP.DR


Malaria is a devastating infectious disease caused by parasites of the genus Plasmodia. Nearly half of the world's population, lives in areas where malaria is endemic and roughly one million deaths in children are reported every year. During the first decade of this century a dozen or so new drugs entered the clinical development and also new ways of accelerating the discovery of antimalarials have arisen. However, emerging drug resistance represents a tremendous challenge for the eradication of malaria. Under the current situation, the development of new antimalarials is urgently needed, as well as the concomitant search for new drug targets. In this sense, the food vacuole proteases involved in hemoglobin degradation during the intraerythrocytic stage of the parasite's life cycle have been described as promising drug targets. Among this group of proteases, the cysteine proteases falcipain 2 (FP-2) and falcipain 3 (FP-3), considered as a key hemoglobinases, have been extensively targeted for the development of novel antimalarials. To date, most works, however, have focused on the identification of competitive inhibitors against both enzymes and none has explored the allosteric inhibition, which was demonstrated for FP-2 in recent years. Our project will be devoted, then, to the identification of both competitive and allosteric inhibitors of FP-2 and FP-3 through an integrated in silico and experimental approach. We will combined state-of-the-art molecular modeling tools, such as docking, MD simulations, free energy and cross-correlation analysis to provide structural information on the binding modes of the inhibitors identified in our work, as well as a structural and energetic explanation of the allosteric modulation of FP-2 and, presumably, of FP-3. We expect to provide a framework to exploit the allosteric modulation of FPs, and its potential towards the design of more specific drugs.

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Scientific publications (9)
(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)
ALVAREZ, LILIAN HERNANDEZ; BARRETO GOMES, DIEGO ENRY; HERNANDEZ GONZALEZ, JORGE ENRIQUE; PASCUTTI, PEDRO GERALDO. Dissecting a novel allosteric mechanism of cruzain: A computer-aided approach. PLoS One, v. 14, n. 1, . (16/24587-9, 18/03911-8)
HERNANDEZ GONZALEZ, JORGE ENRIQUE; ALVAREZ, LILIAN HERNANDEZ; PASCUTTI, PEDRO GERALDO; LEITE, VITOR B. P.. Prediction of Noncompetitive Inhibitor Binding Mode Reveals Promising Site for Allosteric Modulation of Falcipain-2. Journal of Physical Chemistry B, v. 123, n. 34, SI, p. 7327-7342, . (16/24587-9, 18/03911-8)
GONZALEZ, JORGE ENRIQUE HERNANDEZ; ALVAREZ, LILIAN HERNANDEZ; LEITE, VITOR B. P.; PASCUTTI, PEDRO GERALDO. Water Bridges Play a Key Role in Affinity and Selectivity for Malarial Protease Falcipain-2. JOURNAL OF CHEMICAL INFORMATION AND MODELING, v. 60, n. 11, p. 5499-5512, . (16/24587-9, 18/25311-2, 18/03911-8)
HERNANDEZ-ALVAREZ, LILIAN; OLIVEIRA JR, ANTONIO B.; HERNANDEZ-GONZALEZ, JORGE ENRIQUE; CHAHINE, JORGE; PASCUTTI, PEDRO GERALDO; DE ARAUJO, ALEXANDRE SUMAN; DE SOUZA, FATIMA PEREIRA. Computational study on the allosteric mechanism of Leishmania major IF4E-1 by 4E-interacting protein-1: Unravelling the determinants of m(7)GTP cap recognition. COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL, v. 19, p. 2027-2044, . (10/18169-3, 16/24587-9, 18/03911-8)
HERNANDEZ-GONZALEZ, JORGE E.; SALAS-SARDUY, EMIR; HERNANDEZ RAMIREZ, LUISA F.; PASCUAL, MARIA J.; ALVAREZ, DIEGO E.; PABON, ADRIANA; LEITE, VITOR B. P.; PASCUTTI, PEDRO G.; VALIENTE, PEDRO A.. Identification of (4-(9H-fluoren-9-yl) piperazin-1-yl) methanone derivatives as falcipain 2 inhibitors active against Plasmodium falciparum cultures. BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, v. 1862, n. 12, p. 2911-2923, . (16/24587-9)
RODRIGUES, CAIO H. P.; HERNANDEZ-GONZALEZ, JORGE E.; PEDRINA, NATALIA J.; LEITE, VITOR B. P.; BRUNI, ALINE T.. In silico Evaluation of Cucurbit[6]uril as a Potential Detector for Cocaine and Its Adulterants Lidocaine, Caffeine, and Procaine. Journal of the Brazilian Chemical Society, v. 32, n. 4, p. 800-810, . (16/19766-1, 16/24587-9)
MARIUTTI, RICARDO B.; HERNANDEZ-GONZALEZ, JORGE E.; NASCIMENTO, ANDREY F. Z.; DE MORAIS, MARIANA A. B.; MURAKAMI, MARIO T.; CARARETO, CLAUDIA M. A.; ARNI, RAGHUVIR K.. A single P115Q mutation modulates specificity in the Corynebacterium pseudotuberculosis arginine repressor. BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, v. 1864, n. 7, . (18/07977-3, 15/13765-0, 16/19995-0, 15/18868-2, 18/10736-8, 16/24587-9)
HERNANDEZ GONZALEZ, JORGE ENRIQUE; ALVAREZ, LILIAN HERNANDEZ; PASCUTTI, PEDRO GERALDO; VALIENTE, PEDRO A.. Predicting binding modes of reversible peptide-based inhibitors of falcipain-2 consistent with structure-activity relationships. PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS, v. 85, n. 9, p. 1666-1683, . (16/24587-9)
HERNANDEZ GONZALEZ, JORGE ENRIQUE; SALAS-SARDUY, EMIR; HERNANDEZ ALVAREZ, LILIAN; BARRETO GOMES, DIEGO ENRY; PASCUTTI, PEDRO GERALDO; OOSTENBRINK, CHRIS; LEITE, VITOR B. P.. In silico identification of noncompetitive inhibitors targeting an uncharacterized allosteric site of falcipain-2. Journal of Computer-Aided Molecular Design, v. 35, n. 10, p. 1067-1079, . (16/24587-9, 20/10214-1, 16/19766-1, 18/03911-8, 19/22540-3)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
GONZÁLEZ, Jorge Enrique Hernández. Computational strategies for selective inhibition of falcipain-2. 2020. Doctoral Thesis - Universidade Estadual Paulista (Unesp). Instituto de Biociências Letras e Ciências Exatas. São José do Rio Preto São José do Rio Preto.

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