Targeting Intrinsically Disordered Proteins through Dynamic Interactions
Intrinsically disordered proteins (IDPs) are over-represented in major disease pathways and have attracted significant interest in understanding if and how they may be targeted using small molecules for therapeutic purposes. While most existing studies have focused on extending the traditional struc...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-05-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/10/5/743 |
| _version_ | 1797568307268681728 |
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| author | Jianlin Chen Xiaorong Liu Jianhan Chen |
| author_facet | Jianlin Chen Xiaorong Liu Jianhan Chen |
| author_sort | Jianlin Chen |
| collection | DOAJ |
| description | Intrinsically disordered proteins (IDPs) are over-represented in major disease pathways and have attracted significant interest in understanding if and how they may be targeted using small molecules for therapeutic purposes. While most existing studies have focused on extending the traditional structure-centric drug design strategies and emphasized exploring pre-existing structure features of IDPs for specific binding, several examples have also emerged to suggest that small molecules could achieve specificity in binding IDPs and affect their function through dynamic and transient interactions. These dynamic interactions can modulate the disordered conformational ensemble and often lead to modest compaction to shield functionally important interaction sites. Much work remains to be done on further elucidation of the molecular basis of the dynamic small molecule–IDP interaction and determining how it can be exploited for targeting IDPs in practice. These efforts will rely critically on an integrated experimental and computational framework for disordered protein ensemble characterization. In particular, exciting advances have been made in recent years in enhanced sampling techniques, Graphic Processing Unit (GPU)-computing, and protein force field optimization, which have now allowed rigorous physics-based atomistic simulations to generate reliable structure ensembles for nontrivial IDPs of modest sizes. Such de novo atomistic simulations will play crucial roles in exploring the exciting opportunity of targeting IDPs through dynamic interactions. |
| first_indexed | 2024-03-10T19:55:36Z |
| format | Article |
| id | doaj.art-82ed25efb60a4ccc924eed96d5390299 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T19:55:36Z |
| publishDate | 2020-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-82ed25efb60a4ccc924eed96d53902992023-11-20T00:00:38ZengMDPI AGBiomolecules2218-273X2020-05-0110574310.3390/biom10050743Targeting Intrinsically Disordered Proteins through Dynamic InteractionsJianlin Chen0Xiaorong Liu1Jianhan Chen2Department of Hematology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou 318000, Zhejiang, ChinaDepartment of Chemistry, University of Massachusetts, Amherst, MA 01003, USADepartment of Chemistry, University of Massachusetts, Amherst, MA 01003, USAIntrinsically disordered proteins (IDPs) are over-represented in major disease pathways and have attracted significant interest in understanding if and how they may be targeted using small molecules for therapeutic purposes. While most existing studies have focused on extending the traditional structure-centric drug design strategies and emphasized exploring pre-existing structure features of IDPs for specific binding, several examples have also emerged to suggest that small molecules could achieve specificity in binding IDPs and affect their function through dynamic and transient interactions. These dynamic interactions can modulate the disordered conformational ensemble and often lead to modest compaction to shield functionally important interaction sites. Much work remains to be done on further elucidation of the molecular basis of the dynamic small molecule–IDP interaction and determining how it can be exploited for targeting IDPs in practice. These efforts will rely critically on an integrated experimental and computational framework for disordered protein ensemble characterization. In particular, exciting advances have been made in recent years in enhanced sampling techniques, Graphic Processing Unit (GPU)-computing, and protein force field optimization, which have now allowed rigorous physics-based atomistic simulations to generate reliable structure ensembles for nontrivial IDPs of modest sizes. Such de novo atomistic simulations will play crucial roles in exploring the exciting opportunity of targeting IDPs through dynamic interactions.https://www.mdpi.com/2218-273X/10/5/743aggregationcancerdisordered ensembledrug designenhanced samplingGPU computing |
| spellingShingle | Jianlin Chen Xiaorong Liu Jianhan Chen Targeting Intrinsically Disordered Proteins through Dynamic Interactions Biomolecules aggregation cancer disordered ensemble drug design enhanced sampling GPU computing |
| title | Targeting Intrinsically Disordered Proteins through Dynamic Interactions |
| title_full | Targeting Intrinsically Disordered Proteins through Dynamic Interactions |
| title_fullStr | Targeting Intrinsically Disordered Proteins through Dynamic Interactions |
| title_full_unstemmed | Targeting Intrinsically Disordered Proteins through Dynamic Interactions |
| title_short | Targeting Intrinsically Disordered Proteins through Dynamic Interactions |
| title_sort | targeting intrinsically disordered proteins through dynamic interactions |
| topic | aggregation cancer disordered ensemble drug design enhanced sampling GPU computing |
| url | https://www.mdpi.com/2218-273X/10/5/743 |
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