Technologies for Direct Detection of Covalent Protein–Drug Adducts
In the past two decades, drug candidates with a covalent binding mode have gained the interest of medicinal chemists, as several covalent anticancer drugs have successfully reached the clinic. As a covalent binding mode changes the relevant parameters to rank inhibitor potency and investigate struct...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-04-01
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| Series: | Pharmaceuticals |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1424-8247/16/4/547 |
| _version_ | 1797603931480653824 |
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| author | Elma Mons Robbert Q. Kim Monique P. C. Mulder |
| author_facet | Elma Mons Robbert Q. Kim Monique P. C. Mulder |
| author_sort | Elma Mons |
| collection | DOAJ |
| description | In the past two decades, drug candidates with a covalent binding mode have gained the interest of medicinal chemists, as several covalent anticancer drugs have successfully reached the clinic. As a covalent binding mode changes the relevant parameters to rank inhibitor potency and investigate structure-activity relationship (SAR), it is important to gather experimental evidence on the existence of a covalent protein–drug adduct. In this work, we review established methods and technologies for the direct detection of a covalent protein–drug adduct, illustrated with examples from (recent) drug development endeavors. These technologies include subjecting covalent drug candidates to mass spectrometric (MS) analysis, protein crystallography, or monitoring intrinsic spectroscopic properties of the ligand upon covalent adduct formation. Alternatively, chemical modification of the covalent ligand is required to detect covalent adducts by NMR analysis or activity-based protein profiling (ABPP). Some techniques are more informative than others and can also elucidate the modified amino acid residue or bond layout. We will discuss the compatibility of these techniques with reversible covalent binding modes and the possibilities to evaluate reversibility or obtain kinetic parameters. Finally, we expand upon current challenges and future applications. Overall, these analytical techniques present an integral part of covalent drug development in this exciting new era of drug discovery. |
| first_indexed | 2024-03-11T04:39:02Z |
| format | Article |
| id | doaj.art-23183883f9664977ac0095037f4f0750 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-11T04:39:02Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-23183883f9664977ac0095037f4f07502023-11-17T20:50:29ZengMDPI AGPharmaceuticals1424-82472023-04-0116454710.3390/ph16040547Technologies for Direct Detection of Covalent Protein–Drug AdductsElma Mons0Robbert Q. Kim1Monique P. C. Mulder2Department of Cell and Chemical Biology, Leiden University Medical Center, 2300 RC Leiden, The NetherlandsDepartment of Cell and Chemical Biology, Leiden University Medical Center, 2300 RC Leiden, The NetherlandsDepartment of Cell and Chemical Biology, Leiden University Medical Center, 2300 RC Leiden, The NetherlandsIn the past two decades, drug candidates with a covalent binding mode have gained the interest of medicinal chemists, as several covalent anticancer drugs have successfully reached the clinic. As a covalent binding mode changes the relevant parameters to rank inhibitor potency and investigate structure-activity relationship (SAR), it is important to gather experimental evidence on the existence of a covalent protein–drug adduct. In this work, we review established methods and technologies for the direct detection of a covalent protein–drug adduct, illustrated with examples from (recent) drug development endeavors. These technologies include subjecting covalent drug candidates to mass spectrometric (MS) analysis, protein crystallography, or monitoring intrinsic spectroscopic properties of the ligand upon covalent adduct formation. Alternatively, chemical modification of the covalent ligand is required to detect covalent adducts by NMR analysis or activity-based protein profiling (ABPP). Some techniques are more informative than others and can also elucidate the modified amino acid residue or bond layout. We will discuss the compatibility of these techniques with reversible covalent binding modes and the possibilities to evaluate reversibility or obtain kinetic parameters. Finally, we expand upon current challenges and future applications. Overall, these analytical techniques present an integral part of covalent drug development in this exciting new era of drug discovery.https://www.mdpi.com/1424-8247/16/4/547covalent inhibitorschemical probescovalent warheadsmedicinal chemistrydrug discoverydrug development |
| spellingShingle | Elma Mons Robbert Q. Kim Monique P. C. Mulder Technologies for Direct Detection of Covalent Protein–Drug Adducts Pharmaceuticals covalent inhibitors chemical probes covalent warheads medicinal chemistry drug discovery drug development |
| title | Technologies for Direct Detection of Covalent Protein–Drug Adducts |
| title_full | Technologies for Direct Detection of Covalent Protein–Drug Adducts |
| title_fullStr | Technologies for Direct Detection of Covalent Protein–Drug Adducts |
| title_full_unstemmed | Technologies for Direct Detection of Covalent Protein–Drug Adducts |
| title_short | Technologies for Direct Detection of Covalent Protein–Drug Adducts |
| title_sort | technologies for direct detection of covalent protein drug adducts |
| topic | covalent inhibitors chemical probes covalent warheads medicinal chemistry drug discovery drug development |
| url | https://www.mdpi.com/1424-8247/16/4/547 |
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