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Prediction of Noncompetitive Inhibitor Binding Mode Reveals Promising Site for Allosteric Modulation of Falcipain-2

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Autor(es):
Hernandez Gonzalez, Jorge Enrique [1] ; Alvarez, Lilian Hernandez [1] ; Pascutti, Pedro Geraldo [2] ; Leite, Vitor B. P. [3, 1]
Número total de Autores: 4
Afiliação do(s) autor(es):
[1] Univ Estadual Paulista, Inst Biociencias Letras & Ciencias Exatas, Dept Fis, Rua Cristevao Colombo 2265, BR-15054000 Sao Jose Do Rio Preto, SP - Brazil
[2] Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, Lab Dinam & Modelagem Mol, Ave Carlos Chagas Filho 373, CCS Bloco D Sala 30, BR-21941902 Rio De Janeiro - Brazil
[3] Rice Univ, Ctr Theoret Biol Phys, Houston, TX 77005 - USA
Número total de Afiliações: 3
Tipo de documento: Artigo Científico
Fonte: Journal of Physical Chemistry B; v. 123, n. 34, SI, p. 7327-7342, AUG 29 2019.
Citações Web of Science: 0
Resumo

Falcipain-2 (FP-2) is a Plasmodium falciparum cysteine protease that has been extensively targeted to identify novel antimalarials. Remarkably, previous reports have shown that FP-2 can be allosterically modulated and, for a particular noncompetitive chalcone inhibitor, the existing lines of experimental evidence can guide the prediction of its unknown binding mode to the enzyme in a reliable fashion. In this work, we propose a structure of FP-2 in complex with the aforementioned compound that fulfills all of the experimental data, by employing a combination of molecular modeling tools, such as pocket volume measurements, docking, molecular dynamics (MD) simulations, and free energy calculations. Our results show that the studied inhibitor binds a transient pocket occluded in all of the available FP-2 crystal structures and lying in a region previously characterized as a potential allosteric site in related cysteine proteases. In addition, we detected in silico the occurrence of significant community reorganization in FP-2, increased signal transmission between the allosteric pocket and the active site, and change in loop motions and residue pK(a) values upon the compound binding, thus providing insight into the uncharacterized allosteric mechanism. Overall, this study yields valuable predictions for the design of novel allosteric inhibitors against FP-2 and other cysteine proteases. (AU)

Processo FAPESP: 16/24587-9 - Identificação in silico de novos inibidores competitivos e alostéricos das falcipaínas 2 e 3
Beneficiário:Jorge Enrique Hernández González
Linha de fomento: Bolsas no Brasil - Doutorado
Processo FAPESP: 18/03911-8 - Desenho baseado em estrutura de inibidores alostéricos e competitivos da cruzaína
Beneficiário:Lilian Hernández Alvarez
Linha de fomento: Bolsas no Brasil - Doutorado