Shedding Light on the Molecular Recognition of Sub-Kilodalton Macrocyclic Peptides on Thrombin by Supervised Molecular Dynamics
Macrocycles are attractive structures for drug development due to their favorable structural features, potential in binding to targets with flat featureless surfaces, and their ability to disrupt protein–protein interactions. Moreover, large novel highly diverse libraries of low-molecular-weight mac...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-08-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2021.707661/full |
| _version_ | 1819034186475896832 |
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| author | Mahdi Hassankalhori Giovanni Bolcato Maicol Bissaro Mattia Sturlese Stefano Moro |
| author_facet | Mahdi Hassankalhori Giovanni Bolcato Maicol Bissaro Mattia Sturlese Stefano Moro |
| author_sort | Mahdi Hassankalhori |
| collection | DOAJ |
| description | Macrocycles are attractive structures for drug development due to their favorable structural features, potential in binding to targets with flat featureless surfaces, and their ability to disrupt protein–protein interactions. Moreover, large novel highly diverse libraries of low-molecular-weight macrocycles with therapeutically favorable characteristics have been recently established. Considering the mentioned facts, having a validated, fast, and accurate computational protocol for studying the molecular recognition and binding mode of this interesting new class of macrocyclic peptides deemed to be helpful as well as insightful in the quest of accelerating drug discovery. To that end, the ability of the in-house supervised molecular dynamics protocol called SuMD in the reproduction of the X-ray crystallography final binding state of a macrocyclic non-canonical tetrapeptide—from a novel library of 8,988 sub-kilodalton macrocyclic peptides—in the thrombin active site was successfully validated. A comparable binding mode with the minimum root-mean-square deviation (RMSD) of 1.4 Å at simulation time point 71.6 ns was achieved. This method validation study extended the application domain of the SuMD sampling method for computationally cheap, fast but accurate, and insightful macrocycle–protein molecular recognition studies. |
| first_indexed | 2024-12-21T07:29:44Z |
| format | Article |
| id | doaj.art-b26cd90a1a39409c883400c6077f5cb5 |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-12-21T07:29:44Z |
| publishDate | 2021-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-b26cd90a1a39409c883400c6077f5cb52022-12-21T19:11:35ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2021-08-01810.3389/fmolb.2021.707661707661Shedding Light on the Molecular Recognition of Sub-Kilodalton Macrocyclic Peptides on Thrombin by Supervised Molecular DynamicsMahdi HassankalhoriGiovanni BolcatoMaicol BissaroMattia SturleseStefano MoroMacrocycles are attractive structures for drug development due to their favorable structural features, potential in binding to targets with flat featureless surfaces, and their ability to disrupt protein–protein interactions. Moreover, large novel highly diverse libraries of low-molecular-weight macrocycles with therapeutically favorable characteristics have been recently established. Considering the mentioned facts, having a validated, fast, and accurate computational protocol for studying the molecular recognition and binding mode of this interesting new class of macrocyclic peptides deemed to be helpful as well as insightful in the quest of accelerating drug discovery. To that end, the ability of the in-house supervised molecular dynamics protocol called SuMD in the reproduction of the X-ray crystallography final binding state of a macrocyclic non-canonical tetrapeptide—from a novel library of 8,988 sub-kilodalton macrocyclic peptides—in the thrombin active site was successfully validated. A comparable binding mode with the minimum root-mean-square deviation (RMSD) of 1.4 Å at simulation time point 71.6 ns was achieved. This method validation study extended the application domain of the SuMD sampling method for computationally cheap, fast but accurate, and insightful macrocycle–protein molecular recognition studies.https://www.frontiersin.org/articles/10.3389/fmolb.2021.707661/fullmolecular recognitionmacrocyclicsupervised molecular dynamicsthrombintetrapeptide |
| spellingShingle | Mahdi Hassankalhori Giovanni Bolcato Maicol Bissaro Mattia Sturlese Stefano Moro Shedding Light on the Molecular Recognition of Sub-Kilodalton Macrocyclic Peptides on Thrombin by Supervised Molecular Dynamics Frontiers in Molecular Biosciences molecular recognition macrocyclic supervised molecular dynamics thrombin tetrapeptide |
| title | Shedding Light on the Molecular Recognition of Sub-Kilodalton Macrocyclic Peptides on Thrombin by Supervised Molecular Dynamics |
| title_full | Shedding Light on the Molecular Recognition of Sub-Kilodalton Macrocyclic Peptides on Thrombin by Supervised Molecular Dynamics |
| title_fullStr | Shedding Light on the Molecular Recognition of Sub-Kilodalton Macrocyclic Peptides on Thrombin by Supervised Molecular Dynamics |
| title_full_unstemmed | Shedding Light on the Molecular Recognition of Sub-Kilodalton Macrocyclic Peptides on Thrombin by Supervised Molecular Dynamics |
| title_short | Shedding Light on the Molecular Recognition of Sub-Kilodalton Macrocyclic Peptides on Thrombin by Supervised Molecular Dynamics |
| title_sort | shedding light on the molecular recognition of sub kilodalton macrocyclic peptides on thrombin by supervised molecular dynamics |
| topic | molecular recognition macrocyclic supervised molecular dynamics thrombin tetrapeptide |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2021.707661/full |
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