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Inhibitor Trapping in N-Myristoyltransferases as a Mechanism for Drug Potency
Predicting inhibitor potency is critical in drug design and development, yet it has remained one of computational biology’s biggest unresolved challenges. Here, we show that in the case of the N-myristoyltransferase (NMT), this problem could be traced to the mechanisms by which the NMT enzyme is inh...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10380619/ https://www.ncbi.nlm.nih.gov/pubmed/37511367 http://dx.doi.org/10.3390/ijms241411610 |
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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 | Predicting inhibitor potency is critical in drug design and development, yet it has remained one of computational biology’s biggest unresolved challenges. Here, we show that in the case of the N-myristoyltransferase (NMT), this problem could be traced to the mechanisms by which the NMT enzyme is inhibited. NMT adopts open or closed conformations necessary for orchestrating the different steps of the catalytic process. The results indicate that the potency of the NMT inhibitors is determined by their ability to stabilize the enzyme conformation in the closed state, and that in this state, the small molecules themselves are trapped and locked inside the structure of the enzyme, creating a significant barrier for their dissociation. By using molecular dynamics simulations, we demonstrate that the conformational stabilization of the protein molecule in its closed form is highly correlated with the ligands activity and can be used to predict their potency. Hence, predicting inhibitor potency in silico might depend on modeling the conformational changes of the protein molecule upon binding of the ligand rather than estimating the changes in free binding energy that arise from their interaction. |
format | Online Article Text |
id | pubmed-10380619 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-103806192023-07-29 Inhibitor Trapping in N-Myristoyltransferases as a Mechanism for Drug Potency Spassov, Danislav S. Atanasova, Mariyana Doytchinova, Irini Int J Mol Sci Article Predicting inhibitor potency is critical in drug design and development, yet it has remained one of computational biology’s biggest unresolved challenges. Here, we show that in the case of the N-myristoyltransferase (NMT), this problem could be traced to the mechanisms by which the NMT enzyme is inhibited. NMT adopts open or closed conformations necessary for orchestrating the different steps of the catalytic process. The results indicate that the potency of the NMT inhibitors is determined by their ability to stabilize the enzyme conformation in the closed state, and that in this state, the small molecules themselves are trapped and locked inside the structure of the enzyme, creating a significant barrier for their dissociation. By using molecular dynamics simulations, we demonstrate that the conformational stabilization of the protein molecule in its closed form is highly correlated with the ligands activity and can be used to predict their potency. Hence, predicting inhibitor potency in silico might depend on modeling the conformational changes of the protein molecule upon binding of the ligand rather than estimating the changes in free binding energy that arise from their interaction. MDPI 2023-07-18 /pmc/articles/PMC10380619/ /pubmed/37511367 http://dx.doi.org/10.3390/ijms241411610 Text en © 2023 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 Spassov, Danislav S. Atanasova, Mariyana Doytchinova, Irini Inhibitor Trapping in N-Myristoyltransferases as a Mechanism for Drug Potency |
title | Inhibitor Trapping in N-Myristoyltransferases as a Mechanism for Drug Potency |
title_full | Inhibitor Trapping in N-Myristoyltransferases as a Mechanism for Drug Potency |
title_fullStr | Inhibitor Trapping in N-Myristoyltransferases as a Mechanism for Drug Potency |
title_full_unstemmed | Inhibitor Trapping in N-Myristoyltransferases as a Mechanism for Drug Potency |
title_short | Inhibitor Trapping in N-Myristoyltransferases as a Mechanism for Drug Potency |
title_sort | inhibitor trapping in n-myristoyltransferases as a mechanism for drug potency |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10380619/ https://www.ncbi.nlm.nih.gov/pubmed/37511367 http://dx.doi.org/10.3390/ijms241411610 |
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