Studies of 4-arylthiazolylhydrazones derived from 1-indanones as Trypanosoma cruzi squalene epoxidase inhibitors by molecular simulations

Chagas disease or American trypanosomiasis is a parasitic disease caused by the protozoan Trypanosoma cruzi. Its squalene epoxidase (SE) is a target for drug design and development because it is a key enzyme in the biosynthetic pathway of ergosterol, which is essential for the life cycle of the para...

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Publicado:	2018
Materias:	Crystal structure Enzymes Free energy Life cycle Molecular dynamics Biochemical interactions Biosynthetic pathway Molecular simulations Pharmacophore modeling Protozoan Trypanosoma Structural similarity Superposition analysis Theoretical calculations Binding energy enzyme inhibitor hydrazone derivative indan derivative squalene monooxygenase amino acid sequence antagonists and inhibitors chemistry drug design enzymology metabolism molecular docking molecular dynamics molecular model protein conformation thermodynamics Trypanosoma cruzi Amino Acid Sequence Drug Design Enzyme Inhibitors Hydrazones Indans Models, Molecular Molecular Docking Simulation Molecular Dynamics Simulation Protein Conformation Squalene Monooxygenase Thermodynamics
Acceso en línea:	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_14770520_v16_n44_p8525_Noguera http://hdl.handle.net/20.500.12110/paper_14770520_v16_n44_p8525_Noguera
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

id	paper:paper_14770520_v16_n44_p8525_Noguera
record_format	dspace
spelling	paper:paper_14770520_v16_n44_p8525_Noguera2023-06-08T16:18:05Z Studies of 4-arylthiazolylhydrazones derived from 1-indanones as Trypanosoma cruzi squalene epoxidase inhibitors by molecular simulations Crystal structure Enzymes Free energy Life cycle Molecular dynamics Biochemical interactions Biosynthetic pathway Molecular simulations Pharmacophore modeling Protozoan Trypanosoma Structural similarity Superposition analysis Theoretical calculations Binding energy enzyme inhibitor hydrazone derivative indan derivative squalene monooxygenase amino acid sequence antagonists and inhibitors chemistry drug design enzymology metabolism molecular docking molecular dynamics molecular model protein conformation thermodynamics Trypanosoma cruzi Amino Acid Sequence Drug Design Enzyme Inhibitors Hydrazones Indans Models, Molecular Molecular Docking Simulation Molecular Dynamics Simulation Protein Conformation Squalene Monooxygenase Thermodynamics Trypanosoma cruzi Chagas disease or American trypanosomiasis is a parasitic disease caused by the protozoan Trypanosoma cruzi. Its squalene epoxidase (SE) is a target for drug design and development because it is a key enzyme in the biosynthetic pathway of ergosterol, which is essential for the life cycle of the parasite. Previously, we reported that some 4-arylthiazolylhydrazones derived from 1-indanones (TZHs) active against T. cruzi are able to accumulate squalene probably by SE inhibition. In this work, we performed a series of theoretical studies to verify that TZHs act as inhibitors of this enzyme. Since the crystal structure of SE is unknown for all species, we built a 3D enzyme model of T. cruzi SE by homology modeling. Based on this model, we carried out docking, molecular dynamics, and MM/PBSA calculations and the results were compared with those found for the reference inhibitor compound terbinafine (Tbf). The binding free energy values allowed the discrimination between accumulators and non-accumulators of squalene compounds, in agreement with the experimental findings. Pairwise residue free energy decomposition showed that the key amino acids involved in inhibitor binding for TZHs and Tbf were the same. Also, molecular superposition analysis between these compounds revealed high structural similarity. In addition, we proposed a pharmacophore model for T. cruzi SE inhibitors, which confirmed that TZHs and Tbf share chemical features with respect to their biochemical interaction characteristics at similar positions in 3D space. All theoretical calculations suggest that the experimentally observed squalene accumulation is produced by T. cruzi SE inhibition. © The Royal Society of Chemistry. 2018 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_14770520_v16_n44_p8525_Noguera http://hdl.handle.net/20.500.12110/paper_14770520_v16_n44_p8525_Noguera
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	Crystal structure Enzymes Free energy Life cycle Molecular dynamics Biochemical interactions Biosynthetic pathway Molecular simulations Pharmacophore modeling Protozoan Trypanosoma Structural similarity Superposition analysis Theoretical calculations Binding energy enzyme inhibitor hydrazone derivative indan derivative squalene monooxygenase amino acid sequence antagonists and inhibitors chemistry drug design enzymology metabolism molecular docking molecular dynamics molecular model protein conformation thermodynamics Trypanosoma cruzi Amino Acid Sequence Drug Design Enzyme Inhibitors Hydrazones Indans Models, Molecular Molecular Docking Simulation Molecular Dynamics Simulation Protein Conformation Squalene Monooxygenase Thermodynamics Trypanosoma cruzi
spellingShingle	Crystal structure Enzymes Free energy Life cycle Molecular dynamics Biochemical interactions Biosynthetic pathway Molecular simulations Pharmacophore modeling Protozoan Trypanosoma Structural similarity Superposition analysis Theoretical calculations Binding energy enzyme inhibitor hydrazone derivative indan derivative squalene monooxygenase amino acid sequence antagonists and inhibitors chemistry drug design enzymology metabolism molecular docking molecular dynamics molecular model protein conformation thermodynamics Trypanosoma cruzi Amino Acid Sequence Drug Design Enzyme Inhibitors Hydrazones Indans Models, Molecular Molecular Docking Simulation Molecular Dynamics Simulation Protein Conformation Squalene Monooxygenase Thermodynamics Trypanosoma cruzi Studies of 4-arylthiazolylhydrazones derived from 1-indanones as Trypanosoma cruzi squalene epoxidase inhibitors by molecular simulations
topic_facet	Crystal structure Enzymes Free energy Life cycle Molecular dynamics Biochemical interactions Biosynthetic pathway Molecular simulations Pharmacophore modeling Protozoan Trypanosoma Structural similarity Superposition analysis Theoretical calculations Binding energy enzyme inhibitor hydrazone derivative indan derivative squalene monooxygenase amino acid sequence antagonists and inhibitors chemistry drug design enzymology metabolism molecular docking molecular dynamics molecular model protein conformation thermodynamics Trypanosoma cruzi Amino Acid Sequence Drug Design Enzyme Inhibitors Hydrazones Indans Models, Molecular Molecular Docking Simulation Molecular Dynamics Simulation Protein Conformation Squalene Monooxygenase Thermodynamics Trypanosoma cruzi
description	Chagas disease or American trypanosomiasis is a parasitic disease caused by the protozoan Trypanosoma cruzi. Its squalene epoxidase (SE) is a target for drug design and development because it is a key enzyme in the biosynthetic pathway of ergosterol, which is essential for the life cycle of the parasite. Previously, we reported that some 4-arylthiazolylhydrazones derived from 1-indanones (TZHs) active against T. cruzi are able to accumulate squalene probably by SE inhibition. In this work, we performed a series of theoretical studies to verify that TZHs act as inhibitors of this enzyme. Since the crystal structure of SE is unknown for all species, we built a 3D enzyme model of T. cruzi SE by homology modeling. Based on this model, we carried out docking, molecular dynamics, and MM/PBSA calculations and the results were compared with those found for the reference inhibitor compound terbinafine (Tbf). The binding free energy values allowed the discrimination between accumulators and non-accumulators of squalene compounds, in agreement with the experimental findings. Pairwise residue free energy decomposition showed that the key amino acids involved in inhibitor binding for TZHs and Tbf were the same. Also, molecular superposition analysis between these compounds revealed high structural similarity. In addition, we proposed a pharmacophore model for T. cruzi SE inhibitors, which confirmed that TZHs and Tbf share chemical features with respect to their biochemical interaction characteristics at similar positions in 3D space. All theoretical calculations suggest that the experimentally observed squalene accumulation is produced by T. cruzi SE inhibition. © The Royal Society of Chemistry.
title	Studies of 4-arylthiazolylhydrazones derived from 1-indanones as Trypanosoma cruzi squalene epoxidase inhibitors by molecular simulations
title_short	Studies of 4-arylthiazolylhydrazones derived from 1-indanones as Trypanosoma cruzi squalene epoxidase inhibitors by molecular simulations
title_full	Studies of 4-arylthiazolylhydrazones derived from 1-indanones as Trypanosoma cruzi squalene epoxidase inhibitors by molecular simulations
title_fullStr	Studies of 4-arylthiazolylhydrazones derived from 1-indanones as Trypanosoma cruzi squalene epoxidase inhibitors by molecular simulations
title_full_unstemmed	Studies of 4-arylthiazolylhydrazones derived from 1-indanones as Trypanosoma cruzi squalene epoxidase inhibitors by molecular simulations
title_sort	studies of 4-arylthiazolylhydrazones derived from 1-indanones as trypanosoma cruzi squalene epoxidase inhibitors by molecular simulations
publishDate	2018
url	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_14770520_v16_n44_p8525_Noguera http://hdl.handle.net/20.500.12110/paper_14770520_v16_n44_p8525_Noguera
_version_	1768545389415235584

Studies of 4-arylthiazolylhydrazones derived from 1-indanones as Trypanosoma cruzi squalene epoxidase inhibitors by molecular simulations

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