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A role of salt bridges in mediating drug potency: A lesson from the N-myristoyltransferase inhibitors
The salt bridge is the strongest non-covalent interaction in nature and is known to participate in protein folding, protein-protein interactions, and molecular recognition. However, the role of salt bridges in the context of drug design has remained not well understood. Here, we report that a common...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9871453/ https://www.ncbi.nlm.nih.gov/pubmed/36703920 http://dx.doi.org/10.3389/fmolb.2022.1066029 |
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author | Spassov, Danislav S. Atanasova, Mariyana Doytchinova, Irini |
author_facet | Spassov, Danislav S. Atanasova, Mariyana Doytchinova, Irini |
author_sort | Spassov, Danislav S. |
collection | PubMed |
description | The salt bridge is the strongest non-covalent interaction in nature and is known to participate in protein folding, protein-protein interactions, and molecular recognition. However, the role of salt bridges in the context of drug design has remained not well understood. Here, we report that a common feature in the mechanism of inhibition of the N-myristoyltransferases (NMT), promising targets for the treatment of protozoan infections and cancer, is the formation of a salt bridge between a positively charged chemical group of the small molecule and the negatively charged C-terminus of the enzyme. Substituting the inhibitor positively charged amine group with a neutral methylene group prevents the formation of the salt bridge and leads to a dramatic activity loss. Molecular dynamics simulations have revealed that salt bridges stabilize the NMT-ligand complexes by functioning as molecular clips that stabilize the conformation of the protein structure. As such, the creation of salt bridges between the ligands and their protein targets may find an application as a valuable tool in rational drug design. |
format | Online Article Text |
id | pubmed-9871453 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-98714532023-01-25 A role of salt bridges in mediating drug potency: A lesson from the N-myristoyltransferase inhibitors Spassov, Danislav S. Atanasova, Mariyana Doytchinova, Irini Front Mol Biosci Molecular Biosciences The salt bridge is the strongest non-covalent interaction in nature and is known to participate in protein folding, protein-protein interactions, and molecular recognition. However, the role of salt bridges in the context of drug design has remained not well understood. Here, we report that a common feature in the mechanism of inhibition of the N-myristoyltransferases (NMT), promising targets for the treatment of protozoan infections and cancer, is the formation of a salt bridge between a positively charged chemical group of the small molecule and the negatively charged C-terminus of the enzyme. Substituting the inhibitor positively charged amine group with a neutral methylene group prevents the formation of the salt bridge and leads to a dramatic activity loss. Molecular dynamics simulations have revealed that salt bridges stabilize the NMT-ligand complexes by functioning as molecular clips that stabilize the conformation of the protein structure. As such, the creation of salt bridges between the ligands and their protein targets may find an application as a valuable tool in rational drug design. Frontiers Media S.A. 2023-01-10 /pmc/articles/PMC9871453/ /pubmed/36703920 http://dx.doi.org/10.3389/fmolb.2022.1066029 Text en Copyright © 2023 Spassov, Atanasova and Doytchinova. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Molecular Biosciences Spassov, Danislav S. Atanasova, Mariyana Doytchinova, Irini A role of salt bridges in mediating drug potency: A lesson from the N-myristoyltransferase inhibitors |
title | A role of salt bridges in mediating drug potency: A lesson from the N-myristoyltransferase inhibitors |
title_full | A role of salt bridges in mediating drug potency: A lesson from the N-myristoyltransferase inhibitors |
title_fullStr | A role of salt bridges in mediating drug potency: A lesson from the N-myristoyltransferase inhibitors |
title_full_unstemmed | A role of salt bridges in mediating drug potency: A lesson from the N-myristoyltransferase inhibitors |
title_short | A role of salt bridges in mediating drug potency: A lesson from the N-myristoyltransferase inhibitors |
title_sort | role of salt bridges in mediating drug potency: a lesson from the n-myristoyltransferase inhibitors |
topic | Molecular Biosciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9871453/ https://www.ncbi.nlm.nih.gov/pubmed/36703920 http://dx.doi.org/10.3389/fmolb.2022.1066029 |
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