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

Autor(es)

Hernandez Gonzalez, Jorge Enrique ; Alvarez, Lilian Hernandez ; Pascutti, Pedro Geraldo ; Leite, Vitor B. P.

• Tipo de documento: Artigo Científico
• Fonte: Journal of Physical Chemistry B; v. 123, n. 34, p. 16-pg., 2019-08-29.

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