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Homology Modeling of the Human P-glycoprotein (ABCB1) and Insights into Ligand Binding through Molecular Docking Studies

The ABCB1 transporter also known as P-glycoprotein (P-gp) is a transmembrane protein belonging to the ATP binding cassette super-family of transporters; it is a xenobiotic efflux pump that limits intracellular drug accumulation by pumping the compounds out of cells. P-gp contributes to a decrease of...

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Autores principales: Mora Lagares, Liadys, Minovski, Nikola, Caballero Alfonso, Ana Yisel, Benfenati, Emilio, Wellens, Sara, Culot, Maxime, Gosselet, Fabien, Novič, Marjana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312539/
https://www.ncbi.nlm.nih.gov/pubmed/32517082
http://dx.doi.org/10.3390/ijms21114058
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author Mora Lagares, Liadys
Minovski, Nikola
Caballero Alfonso, Ana Yisel
Benfenati, Emilio
Wellens, Sara
Culot, Maxime
Gosselet, Fabien
Novič, Marjana
author_facet Mora Lagares, Liadys
Minovski, Nikola
Caballero Alfonso, Ana Yisel
Benfenati, Emilio
Wellens, Sara
Culot, Maxime
Gosselet, Fabien
Novič, Marjana
author_sort Mora Lagares, Liadys
collection PubMed
description The ABCB1 transporter also known as P-glycoprotein (P-gp) is a transmembrane protein belonging to the ATP binding cassette super-family of transporters; it is a xenobiotic efflux pump that limits intracellular drug accumulation by pumping the compounds out of cells. P-gp contributes to a decrease of toxicity and possesses broad substrate specificity. It is involved in the failure of numerous anticancer and antiviral chemotherapies due to the multidrug resistance (MDR) phenomenon, where it removes the chemotherapeutics out of the targeted cells. Understanding the details of the ligand–P-gp interaction is therefore crucial for the development of drugs that might overcome the MRD phenomenon and for obtaining a more effective prediction of the toxicity of certain compounds. In this work, an in silico modeling was performed using homology modeling and molecular docking methods with the aim of better understanding the ligand–P-gp interactions. Based on different mouse P-gp structural templates from the PDB repository, a 3D model of the human P-gp (hP-gp) was constructed by means of protein homology modeling. The homology model was then used to perform molecular docking calculations on a set of thirteen compounds, including some well-known compounds that interact with P-gp as substrates, inhibitors, or both. The sum of ranking differences (SRD) was employed for the comparison of the different scoring functions used in the docking calculations. A consensus-ranking scheme was employed for the selection of the top-ranked pose for each docked ligand. The docking results showed that a high number of π interactions, mainly π–sigma, π–alkyl, and π–π type of interactions, together with the simultaneous presence of hydrogen bond interactions contribute to the stability of the ligand–protein complex in the binding site. It was also observed that some interacting residues in hP-gp are the same when compared to those observed in a co-crystallized ligand (PBDE-100) with mouse P-gp (PDB ID: 4XWK). Our in silico approach is consistent with available experimental results regarding P-gp efflux transport assay; therefore it could be useful in the prediction of the role of new compounds in systemic toxicity.
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spelling pubmed-73125392020-06-29 Homology Modeling of the Human P-glycoprotein (ABCB1) and Insights into Ligand Binding through Molecular Docking Studies Mora Lagares, Liadys Minovski, Nikola Caballero Alfonso, Ana Yisel Benfenati, Emilio Wellens, Sara Culot, Maxime Gosselet, Fabien Novič, Marjana Int J Mol Sci Article The ABCB1 transporter also known as P-glycoprotein (P-gp) is a transmembrane protein belonging to the ATP binding cassette super-family of transporters; it is a xenobiotic efflux pump that limits intracellular drug accumulation by pumping the compounds out of cells. P-gp contributes to a decrease of toxicity and possesses broad substrate specificity. It is involved in the failure of numerous anticancer and antiviral chemotherapies due to the multidrug resistance (MDR) phenomenon, where it removes the chemotherapeutics out of the targeted cells. Understanding the details of the ligand–P-gp interaction is therefore crucial for the development of drugs that might overcome the MRD phenomenon and for obtaining a more effective prediction of the toxicity of certain compounds. In this work, an in silico modeling was performed using homology modeling and molecular docking methods with the aim of better understanding the ligand–P-gp interactions. Based on different mouse P-gp structural templates from the PDB repository, a 3D model of the human P-gp (hP-gp) was constructed by means of protein homology modeling. The homology model was then used to perform molecular docking calculations on a set of thirteen compounds, including some well-known compounds that interact with P-gp as substrates, inhibitors, or both. The sum of ranking differences (SRD) was employed for the comparison of the different scoring functions used in the docking calculations. A consensus-ranking scheme was employed for the selection of the top-ranked pose for each docked ligand. The docking results showed that a high number of π interactions, mainly π–sigma, π–alkyl, and π–π type of interactions, together with the simultaneous presence of hydrogen bond interactions contribute to the stability of the ligand–protein complex in the binding site. It was also observed that some interacting residues in hP-gp are the same when compared to those observed in a co-crystallized ligand (PBDE-100) with mouse P-gp (PDB ID: 4XWK). Our in silico approach is consistent with available experimental results regarding P-gp efflux transport assay; therefore it could be useful in the prediction of the role of new compounds in systemic toxicity. MDPI 2020-06-05 /pmc/articles/PMC7312539/ /pubmed/32517082 http://dx.doi.org/10.3390/ijms21114058 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Mora Lagares, Liadys
Minovski, Nikola
Caballero Alfonso, Ana Yisel
Benfenati, Emilio
Wellens, Sara
Culot, Maxime
Gosselet, Fabien
Novič, Marjana
Homology Modeling of the Human P-glycoprotein (ABCB1) and Insights into Ligand Binding through Molecular Docking Studies
title Homology Modeling of the Human P-glycoprotein (ABCB1) and Insights into Ligand Binding through Molecular Docking Studies
title_full Homology Modeling of the Human P-glycoprotein (ABCB1) and Insights into Ligand Binding through Molecular Docking Studies
title_fullStr Homology Modeling of the Human P-glycoprotein (ABCB1) and Insights into Ligand Binding through Molecular Docking Studies
title_full_unstemmed Homology Modeling of the Human P-glycoprotein (ABCB1) and Insights into Ligand Binding through Molecular Docking Studies
title_short Homology Modeling of the Human P-glycoprotein (ABCB1) and Insights into Ligand Binding through Molecular Docking Studies
title_sort homology modeling of the human p-glycoprotein (abcb1) and insights into ligand binding through molecular docking studies
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312539/
https://www.ncbi.nlm.nih.gov/pubmed/32517082
http://dx.doi.org/10.3390/ijms21114058
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