Deconstructing allostery by computational assessment of the binding determinants of allosteric PTP1B modulators
Abstract Fragment-based drug discovery is an established methodology for finding hit molecules that can be elaborated into lead compounds. However it is currently challenging to predict whether fragment hits that do not bind to an orthosteric site could be elaborated into allosteric modulators, as i...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-06-01
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| Series: | Communications Chemistry |
| Online Access: | https://doi.org/10.1038/s42004-023-00926-1 |
| _version_ | 1797801517771653120 |
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| author | Adele Hardie Benjamin P. Cossins Silvia Lovera Julien Michel |
| author_facet | Adele Hardie Benjamin P. Cossins Silvia Lovera Julien Michel |
| author_sort | Adele Hardie |
| collection | DOAJ |
| description | Abstract Fragment-based drug discovery is an established methodology for finding hit molecules that can be elaborated into lead compounds. However it is currently challenging to predict whether fragment hits that do not bind to an orthosteric site could be elaborated into allosteric modulators, as in these cases binding does not necessarily translate into a functional effect. We propose a workflow using Markov State Models (MSMs) with steered molecular dynamics (sMD) to assess the allosteric potential of known binders. sMD simulations are employed to sample protein conformational space inaccessible to routine equilibrium MD timescales. Protein conformations sampled by sMD provide starting points for seeded MD simulations, which are combined into MSMs. The methodology is demonstrated on a dataset of protein tyrosine phosphatase 1B ligands. Experimentally confirmed allosteric inhibitors are correctly classified as inhibitors, whereas the deconstructed analogues show reduced inhibitory activity. Analysis of the MSMs provide insights into preferred protein-ligand arrangements that correlate with functional outcomes. The present methodology may find applications for progressing fragments towards lead molecules in FBDD campaigns. |
| first_indexed | 2024-03-13T04:52:24Z |
| format | Article |
| id | doaj.art-95a429127cf947b6b27f85882fc96c79 |
| institution | Directory Open Access Journal |
| issn | 2399-3669 |
| language | English |
| last_indexed | 2024-03-13T04:52:24Z |
| publishDate | 2023-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Chemistry |
| spelling | doaj.art-95a429127cf947b6b27f85882fc96c792023-06-18T11:08:42ZengNature PortfolioCommunications Chemistry2399-36692023-06-01611910.1038/s42004-023-00926-1Deconstructing allostery by computational assessment of the binding determinants of allosteric PTP1B modulatorsAdele Hardie0Benjamin P. Cossins1Silvia Lovera2Julien Michel3EaStChem School of Chemistry, Joseph Black Building, University of EdinburghUCB PharmaUCB PharmaEaStChem School of Chemistry, Joseph Black Building, University of EdinburghAbstract Fragment-based drug discovery is an established methodology for finding hit molecules that can be elaborated into lead compounds. However it is currently challenging to predict whether fragment hits that do not bind to an orthosteric site could be elaborated into allosteric modulators, as in these cases binding does not necessarily translate into a functional effect. We propose a workflow using Markov State Models (MSMs) with steered molecular dynamics (sMD) to assess the allosteric potential of known binders. sMD simulations are employed to sample protein conformational space inaccessible to routine equilibrium MD timescales. Protein conformations sampled by sMD provide starting points for seeded MD simulations, which are combined into MSMs. The methodology is demonstrated on a dataset of protein tyrosine phosphatase 1B ligands. Experimentally confirmed allosteric inhibitors are correctly classified as inhibitors, whereas the deconstructed analogues show reduced inhibitory activity. Analysis of the MSMs provide insights into preferred protein-ligand arrangements that correlate with functional outcomes. The present methodology may find applications for progressing fragments towards lead molecules in FBDD campaigns.https://doi.org/10.1038/s42004-023-00926-1 |
| spellingShingle | Adele Hardie Benjamin P. Cossins Silvia Lovera Julien Michel Deconstructing allostery by computational assessment of the binding determinants of allosteric PTP1B modulators Communications Chemistry |
| title | Deconstructing allostery by computational assessment of the binding determinants of allosteric PTP1B modulators |
| title_full | Deconstructing allostery by computational assessment of the binding determinants of allosteric PTP1B modulators |
| title_fullStr | Deconstructing allostery by computational assessment of the binding determinants of allosteric PTP1B modulators |
| title_full_unstemmed | Deconstructing allostery by computational assessment of the binding determinants of allosteric PTP1B modulators |
| title_short | Deconstructing allostery by computational assessment of the binding determinants of allosteric PTP1B modulators |
| title_sort | deconstructing allostery by computational assessment of the binding determinants of allosteric ptp1b modulators |
| url | https://doi.org/10.1038/s42004-023-00926-1 |
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