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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
Hernandez Gonzalez, Jorge Enrique [1] ; Alvarez, Lilian Hernandez [1] ; Pascutti, Pedro Geraldo [2] ; Leite, Vitor B. P. [3, 1]
Total Authors: 4
Affiliation:
[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
Total Affiliations: 3
Document type: Journal article
Source: Journal of Physical Chemistry B; v. 123, n. 34, SI, p. 7327-7342, AUG 29 2019.
Web of Science Citations: 0
Abstract

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)

FAPESP's process: 16/24587-9 - In silico identification of novel competitive and alosteric inhibitors of falcipains 2 and 3
Grantee:Jorge Enrique Hernández González
Support type: Scholarships in Brazil - Doctorate
FAPESP's process: 18/03911-8 - Structure-based design of competitive and allosteric inhibitors of cruzain
Grantee:Lilian Hernández Alvarez
Support type: Scholarships in Brazil - Doctorate