Pharmacological Chaperones and Protein Conformational Diseases: Approaches of Computational Structural Biology
Whenever a protein fails to fold into its native structure, a profound detrimental effect is likely to occur, and a disease is often developed. Protein conformational disorders arise when proteins adopt abnormal conformations due to a pathological gene variant that turns into gain/loss of function o...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-03-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/6/5819 |
| _version_ | 1797611166345723904 |
|---|---|
| author | Daniela Grasso Silvia Galderisi Annalisa Santucci Andrea Bernini |
| author_facet | Daniela Grasso Silvia Galderisi Annalisa Santucci Andrea Bernini |
| author_sort | Daniela Grasso |
| collection | DOAJ |
| description | Whenever a protein fails to fold into its native structure, a profound detrimental effect is likely to occur, and a disease is often developed. Protein conformational disorders arise when proteins adopt abnormal conformations due to a pathological gene variant that turns into gain/loss of function or improper localization/degradation. Pharmacological chaperones are small molecules restoring the correct folding of a protein suitable for treating conformational diseases. Small molecules like these bind poorly folded proteins similarly to physiological chaperones, bridging non-covalent interactions (hydrogen bonds, electrostatic interactions, and van der Waals contacts) loosened or lost due to mutations. Pharmacological chaperone development involves, among other things, structural biology investigation of the target protein and its misfolding and refolding. Such research can take advantage of computational methods at many stages. Here, we present an up-to-date review of the computational structural biology tools and approaches regarding protein stability evaluation, binding pocket discovery and druggability, drug repurposing, and virtual ligand screening. The tools are presented as organized in an ideal workflow oriented at pharmacological chaperones’ rational design, also with the treatment of rare diseases in mind. |
| first_indexed | 2024-03-11T06:24:59Z |
| format | Article |
| id | doaj.art-5c3efe332b5d4242aa0215942597a0d5 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T06:24:59Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-5c3efe332b5d4242aa0215942597a0d52023-11-17T11:39:30ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-03-01246581910.3390/ijms24065819Pharmacological Chaperones and Protein Conformational Diseases: Approaches of Computational Structural BiologyDaniela Grasso0Silvia Galderisi1Annalisa Santucci2Andrea Bernini3Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, 53100 Siena, ItalyDepartment of Biotechnology, Chemistry, and Pharmacy, University of Siena, 53100 Siena, ItalyDepartment of Biotechnology, Chemistry, and Pharmacy, University of Siena, 53100 Siena, ItalyDepartment of Biotechnology, Chemistry, and Pharmacy, University of Siena, 53100 Siena, ItalyWhenever a protein fails to fold into its native structure, a profound detrimental effect is likely to occur, and a disease is often developed. Protein conformational disorders arise when proteins adopt abnormal conformations due to a pathological gene variant that turns into gain/loss of function or improper localization/degradation. Pharmacological chaperones are small molecules restoring the correct folding of a protein suitable for treating conformational diseases. Small molecules like these bind poorly folded proteins similarly to physiological chaperones, bridging non-covalent interactions (hydrogen bonds, electrostatic interactions, and van der Waals contacts) loosened or lost due to mutations. Pharmacological chaperone development involves, among other things, structural biology investigation of the target protein and its misfolding and refolding. Such research can take advantage of computational methods at many stages. Here, we present an up-to-date review of the computational structural biology tools and approaches regarding protein stability evaluation, binding pocket discovery and druggability, drug repurposing, and virtual ligand screening. The tools are presented as organized in an ideal workflow oriented at pharmacological chaperones’ rational design, also with the treatment of rare diseases in mind.https://www.mdpi.com/1422-0067/24/6/5819pharmacological chaperonesprotein conformational diseasescomputational structural biologyprotein stabilitytransient pocketspocket druggability |
| spellingShingle | Daniela Grasso Silvia Galderisi Annalisa Santucci Andrea Bernini Pharmacological Chaperones and Protein Conformational Diseases: Approaches of Computational Structural Biology International Journal of Molecular Sciences pharmacological chaperones protein conformational diseases computational structural biology protein stability transient pockets pocket druggability |
| title | Pharmacological Chaperones and Protein Conformational Diseases: Approaches of Computational Structural Biology |
| title_full | Pharmacological Chaperones and Protein Conformational Diseases: Approaches of Computational Structural Biology |
| title_fullStr | Pharmacological Chaperones and Protein Conformational Diseases: Approaches of Computational Structural Biology |
| title_full_unstemmed | Pharmacological Chaperones and Protein Conformational Diseases: Approaches of Computational Structural Biology |
| title_short | Pharmacological Chaperones and Protein Conformational Diseases: Approaches of Computational Structural Biology |
| title_sort | pharmacological chaperones and protein conformational diseases approaches of computational structural biology |
| topic | pharmacological chaperones protein conformational diseases computational structural biology protein stability transient pockets pocket druggability |
| url | https://www.mdpi.com/1422-0067/24/6/5819 |
| work_keys_str_mv | AT danielagrasso pharmacologicalchaperonesandproteinconformationaldiseasesapproachesofcomputationalstructuralbiology AT silviagalderisi pharmacologicalchaperonesandproteinconformationaldiseasesapproachesofcomputationalstructuralbiology AT annalisasantucci pharmacologicalchaperonesandproteinconformationaldiseasesapproachesofcomputationalstructuralbiology AT andreabernini pharmacologicalchaperonesandproteinconformationaldiseasesapproachesofcomputationalstructuralbiology |