Journal Article

Dissecting a novel allosteric mechanism of cruzain: A computer-aided approach

Hernández González, Jorge Enrique, Hernández Alvarez, Lilian, Pascutti, Pedro Geraldo, Barreto Gomes, Diego Enry

2019

Overview

Trypanosoma cruzi is the causative agent of Chagas disease, a neglected infection affecting millions of people in tropical regions. There are several chemotherapeutic agents for the treatment of this disease, but most of them are highly toxic and generate resistance. Currently, the development of allosteric inhibitors constitutes a promising research field, since it can improve the accessibility to more selective and less toxic medicines. To date, the allosteric drugs prediction is a state-of-the-art topic in rational structure-based computational design. In this work, a simulation strategy was developed for computational discovery of allosteric inhibitors, and it was applied to cruzain, a promising target and the major cysteine protease of T. cruzi. Molecular dynamics simulations, binding free energy calculations and network-based modelling of residue interactions were combined to characterize and compare molecular distinctive features of the apo form and the cruzain-allosteric inhibitor complexes. By using geometry-based criteria on trajectory snapshots, we predicted two main allosteric sites suitable for drug targeting. The results suggest dissimilar mechanisms exerted by the same allosteric site when binding different potential allosteric inhibitors. Finally, we identified the residues involved in suboptimal paths linking the identified site and the orthosteric site. The present study constitutes the first approximation to the design of cruzain allosteric inhibitors and may serve for future pharmacological intervention. Here, no major effects on active site structure were observed due to compound binding (modification of distance and angles between catalytic residues), which indicates that allosteric regulation in cruzain might be mediated via alterations of its dynamical properties similarly to allosteric inhibition of human cathepsin K (HCatK). The current findings are particularly relevant for the design of allosteric modulators of papain-like cysteine proteases.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Allosteric properties / Allosteric Regulation - drug effects / Angles (geometry) / Binding / Binding sites / Biology and Life Sciences / Catalysis / Catalytic Domain - drug effects / Cathepsin K / Cathepsin K - chemistry / Cathepsin K - drug effects / Chagas disease / Chemotherapy / Computation / Computer and Information Sciences / Computer applications / Computer simulation / Computer-Aided Design / Cruzipain / Cysteine / Cysteine Endopeptidases - chemistry / Cysteine Endopeptidases - metabolism / Cysteine proteinase / Cysteine Proteinase Inhibitors - chemistry / Cysteine Proteinase Inhibitors - pharmacology / Cysteine proteinases / Design / Disease control / Dosage and administration / Drug development / Drug therapy / Enzyme inhibitors / Enzymes / Free energy / Humans / Inhibitors / Kinases / Ligands / Medical treatment / Models, Molecular / Modulators / Molecular dynamics / Molecular Dynamics Simulation / Mutation / Non-pharmacological intervention / Papain / Pharmaceutical industry / Pharmacology / Physical Sciences / Predictions / Protein Conformation / Proteins / Protozoan Proteins - chemistry / Protozoan Proteins - metabolism / Residues / State of the art / Structure-Activity Relationship / Tropical diseases / Tropical environment / Tropical environments / Trypanocidal Agents - chemistry / Trypanocidal Agents - pharmacology / Trypanosoma cruzi - drug effects / Trypanosoma cruzi - metabolism / Vector-borne diseases