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Probing in silico the allosteric inhibition of falcipain 2 as an approach for designing new antimalarials

Grant number: 18/24205-4
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): August 01, 2019
Effective date (End): May 31, 2020
Field of knowledge:Biological Sciences - Biophysics - Molecular Biophysics
Principal researcher:Vitor Barbanti Pereira Leite
Grantee:Jorge Enrique Hernández González
Supervisor abroad: Rommie Amaro
Home 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
Research place: University of California, San Diego (UC San Diego), United States  
Associated to the scholarship:16/24587-9 - In silico identification of novel competitive and alosteric inhibitors of falcipains 2 and 3, BP.DR

Abstract

Malaria is a mosquito-borne infectious disease prevalent in tropical regions, where more than 3.2 billion people live under the risk of infection. Moreover, approximately 216 million cases of malaria and 445 000 deaths were reported in 2016 and, after a period of success in global malaria control, the progress has currently stalled. So far, various antimalarials have been discovered; however, the development of resistance to the available drugs is becoming a major health concern. Therefore, the identification of novel antimalarials is urgently needed. Two C1 cysteine proteases, falcipain-2 and falcipain-3 (FP-2 and FP-3, respectively), have been identified as promising drug targets among the currently known hemoglobinases of Plasmodium falciparum. The aim of this project is to understand in silico the molecular bases of the allosteric inhibition of FP-2 exerted by previously reported compounds as well as others identified throughout the candidate's PhD project. Two methodologies will be employed for that purpose, the Community Analysis (CA) and the Markov State Models (MSMs). In addition, we will apply the previous strategy to existing crystal structures of human cathepsin K (hCatK) in complex with allosteric inhibitors, in order to draw general conclusions on the allosteric mechanisms in the C1 cysteine protease family. Finally, we will propose small chemical modifications on the allosteric hits identified in this project by using relative free energy calculations based on thermodynamic integration (TI) techniques. Overall, the intended project will thoroughly explore the suitability of targeting allosteric sites in FP-2 as an approach to foster the discovery of novel antimalarials.

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