Dissecting a novel allosteric mechanism of cruzain: A computer-aided approach
| Autor: | Lilian Hernández Alvarez, Diego Enry Barreto Gomes, Pedro Geraldo Pascutti, Jorge Enrique Hernández González |
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| Přispěvatelé: | Universidade Estadual Paulista (Unesp), Inst Nacl Metrol Qual & Tecnol INMETRO, Univ Strasbourg, Universidade Federal do Rio de Janeiro (UFRJ) |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Models Molecular Protein Conformation Cathepsin K Protozoan Proteins 01 natural sciences Biochemistry Protein structure Cysteine Proteases Catalytic Domain Macromolecular Structure Analysis Biochemical Simulations Centrality Enzyme Chemistry Free Energy Multidisciplinary Crystallography 010304 chemical physics biology Chemistry Physics Proteases Condensed Matter Physics Cysteine protease Trypanocidal Agents Enzymes Cysteine Endopeptidases Physical Sciences Crystal Structure Medicine Computer-Aided Design Thermodynamics Network Analysis Research Article Computer and Information Sciences Protein Structure Science Trypanosoma cruzi Allosteric regulation Computational biology Cysteine Proteinase Inhibitors Molecular Dynamics Simulation Enzyme Regulation 03 medical and health sciences Structure-Activity Relationship Allosteric Regulation 0103 physical sciences Structure–activity relationship Humans Solid State Physics Molecular Biology Active site Biology and Life Sciences Proteins Computational Biology 030104 developmental biology Targeted drug delivery biology.protein Enzymology Cysteine |
| Zdroj: | PLoS ONE Web of Science Repositório Institucional da UNESP Universidade Estadual Paulista (UNESP) instacron:UNESP PLoS ONE, Vol 14, Iss 1, p e0211227 (2019) |
| ISSN: | 1932-6203 |
| Popis: | Made available in DSpace on 2019-10-04T12:34:52Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-01-25 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) 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. Univ Estadual Paulista, Dept Fis, Inst Biociencias Letras & Ciencias Exatas, Sao Jose Do Rio Preto, SP, Brazil Inst Nacl Metrol Qual & Tecnol INMETRO, Diretoria Metrol Aplicada Ciencias Vida DIMAV, Rio De Janeiro, Brazil Univ Strasbourg, Inst Chim, Strasbourg, France Univ Fed Rio De Janeiro UFRJ, Inst Biofis Carlos Chagas Filho, Rio De Janeiro, Brazil Univ Estadual Paulista, Dept Fis, Inst Biociencias Letras & Ciencias Exatas, Sao Jose Do Rio Preto, SP, Brazil FAPESP: 2018/03911-8 FAPESP: 2016/24587-9 CAPES: 031/2013 PRO-DEFESA 3 CAPES: 613 |
| Databáze: | OpenAIRE |
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