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Molecular Dynamics Simulation of 2-Benzimidazolyl-Urea with DPPC Lipid Membrane and Comparison with a Copper(II) Complex Derivative

Benzimidazole derivatives have gained attention recently due to their wide pharmacological activity acting as anti-inflammatory, hypotensive, analgesic, and anti-aggregatory agents. They are also common ligands in transition metal coordination chemistry, forming complex compounds with enhanced biolo...

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Autores principales: Rossos, Georgios, Hadjikakou, Sotiris K., Kourkoumelis, Nikolaos
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537910/
https://www.ncbi.nlm.nih.gov/pubmed/34677508
http://dx.doi.org/10.3390/membranes11100743
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author Rossos, Georgios
Hadjikakou, Sotiris K.
Kourkoumelis, Nikolaos
author_facet Rossos, Georgios
Hadjikakou, Sotiris K.
Kourkoumelis, Nikolaos
author_sort Rossos, Georgios
collection PubMed
description Benzimidazole derivatives have gained attention recently due to their wide pharmacological activity acting as anti-inflammatory, hypotensive, analgesic, and anti-aggregatory agents. They are also common ligands in transition metal coordination chemistry, forming complex compounds with enhanced biological properties, especially in targeted cancer therapy. A key issue to understand anti-tumour effects is drug permeability through cellular membranes, as poor permeability outcomes can avert further futile drug development. In this work, we conducted atomistic molecular dynamics (MD) simulations and biased MD simulations to explore the interactions of 2-benzimidazolyl-urea with a phospholipid bilayer (dipalmitoylphosphatidylcholine, DPPC) together with a previously synthesized copper(II) complex compound. The aim was to study the permeability of these compounds by assessing their free energy profile along the bilayer normal. The simulations indicated that both the ligand (2-benzimidazolyl-urea, BZIMU) and the complex show a similar behaviour, yielding high energy barriers for the permeation process. However, with increasing concentration of BZIMU, the molecules tend to aggregate and form a cluster, leading to the formation of a pore. Clustering and pore formation can possibly explain the previously observed cytotoxicity of the BZIMU molecule via membrane damage.
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spelling pubmed-85379102021-10-24 Molecular Dynamics Simulation of 2-Benzimidazolyl-Urea with DPPC Lipid Membrane and Comparison with a Copper(II) Complex Derivative Rossos, Georgios Hadjikakou, Sotiris K. Kourkoumelis, Nikolaos Membranes (Basel) Article Benzimidazole derivatives have gained attention recently due to their wide pharmacological activity acting as anti-inflammatory, hypotensive, analgesic, and anti-aggregatory agents. They are also common ligands in transition metal coordination chemistry, forming complex compounds with enhanced biological properties, especially in targeted cancer therapy. A key issue to understand anti-tumour effects is drug permeability through cellular membranes, as poor permeability outcomes can avert further futile drug development. In this work, we conducted atomistic molecular dynamics (MD) simulations and biased MD simulations to explore the interactions of 2-benzimidazolyl-urea with a phospholipid bilayer (dipalmitoylphosphatidylcholine, DPPC) together with a previously synthesized copper(II) complex compound. The aim was to study the permeability of these compounds by assessing their free energy profile along the bilayer normal. The simulations indicated that both the ligand (2-benzimidazolyl-urea, BZIMU) and the complex show a similar behaviour, yielding high energy barriers for the permeation process. However, with increasing concentration of BZIMU, the molecules tend to aggregate and form a cluster, leading to the formation of a pore. Clustering and pore formation can possibly explain the previously observed cytotoxicity of the BZIMU molecule via membrane damage. MDPI 2021-09-28 /pmc/articles/PMC8537910/ /pubmed/34677508 http://dx.doi.org/10.3390/membranes11100743 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Rossos, Georgios
Hadjikakou, Sotiris K.
Kourkoumelis, Nikolaos
Molecular Dynamics Simulation of 2-Benzimidazolyl-Urea with DPPC Lipid Membrane and Comparison with a Copper(II) Complex Derivative
title Molecular Dynamics Simulation of 2-Benzimidazolyl-Urea with DPPC Lipid Membrane and Comparison with a Copper(II) Complex Derivative
title_full Molecular Dynamics Simulation of 2-Benzimidazolyl-Urea with DPPC Lipid Membrane and Comparison with a Copper(II) Complex Derivative
title_fullStr Molecular Dynamics Simulation of 2-Benzimidazolyl-Urea with DPPC Lipid Membrane and Comparison with a Copper(II) Complex Derivative
title_full_unstemmed Molecular Dynamics Simulation of 2-Benzimidazolyl-Urea with DPPC Lipid Membrane and Comparison with a Copper(II) Complex Derivative
title_short Molecular Dynamics Simulation of 2-Benzimidazolyl-Urea with DPPC Lipid Membrane and Comparison with a Copper(II) Complex Derivative
title_sort molecular dynamics simulation of 2-benzimidazolyl-urea with dppc lipid membrane and comparison with a copper(ii) complex derivative
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537910/
https://www.ncbi.nlm.nih.gov/pubmed/34677508
http://dx.doi.org/10.3390/membranes11100743
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