BIreactive: Expanding the Scope of Reactivity Predictions to Propynamides
We present the first comprehensive study on the prediction of reactivity for propynamides. Covalent inhibitors like propynamides often show improved potency, selectivity, and unique pharmacologic properties compared to their non-covalent counterparts. In order to achieve this, it is essential to tun...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-01-01
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| Series: | Pharmaceuticals |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1424-8247/16/1/116 |
| _version_ | 1827622669429768192 |
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| author | Markus R. Hermann Christofer S. Tautermann Peter Sieger Marc A. Grundl Alexander Weber |
| author_facet | Markus R. Hermann Christofer S. Tautermann Peter Sieger Marc A. Grundl Alexander Weber |
| author_sort | Markus R. Hermann |
| collection | DOAJ |
| description | We present the first comprehensive study on the prediction of reactivity for propynamides. Covalent inhibitors like propynamides often show improved potency, selectivity, and unique pharmacologic properties compared to their non-covalent counterparts. In order to achieve this, it is essential to tune the reactivity of the warhead. This study shows how three different in silico methods can predict the in vitro properties of propynamides, a covalent warhead class integrated into approved drugs on the market. Whereas the electrophilicity index is only applicable to individual subclasses of substitutions, adduct formation and transition state energies have a good predictability for the in vitro reactivity with glutathione (GSH). In summary, the reported methods are well suited to estimate the reactivity of propynamides. With this knowledge, the fine tuning of the reactivity is possible which leads to a speed up of the design process of covalent drugs. |
| first_indexed | 2024-03-09T11:28:55Z |
| format | Article |
| id | doaj.art-dd0fd69203ec4014abbc92a1a206eaf6 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T11:28:55Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-dd0fd69203ec4014abbc92a1a206eaf62023-11-30T23:56:01ZengMDPI AGPharmaceuticals1424-82472023-01-0116111610.3390/ph16010116BIreactive: Expanding the Scope of Reactivity Predictions to PropynamidesMarkus R. Hermann0Christofer S. Tautermann1Peter Sieger2Marc A. Grundl3Alexander Weber4Medical Chemistry, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstr. 65, 88397 Biberach an der Riß, GermanyMedical Chemistry, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstr. 65, 88397 Biberach an der Riß, GermanyMedical Chemistry, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstr. 65, 88397 Biberach an der Riß, GermanyMedical Chemistry, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstr. 65, 88397 Biberach an der Riß, GermanyMedical Chemistry, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstr. 65, 88397 Biberach an der Riß, GermanyWe present the first comprehensive study on the prediction of reactivity for propynamides. Covalent inhibitors like propynamides often show improved potency, selectivity, and unique pharmacologic properties compared to their non-covalent counterparts. In order to achieve this, it is essential to tune the reactivity of the warhead. This study shows how three different in silico methods can predict the in vitro properties of propynamides, a covalent warhead class integrated into approved drugs on the market. Whereas the electrophilicity index is only applicable to individual subclasses of substitutions, adduct formation and transition state energies have a good predictability for the in vitro reactivity with glutathione (GSH). In summary, the reported methods are well suited to estimate the reactivity of propynamides. With this knowledge, the fine tuning of the reactivity is possible which leads to a speed up of the design process of covalent drugs.https://www.mdpi.com/1424-8247/16/1/116targeted covalent inhibitorsdrug discoverycovalent warheadsreactivity assessmentglutathionepropynamide |
| spellingShingle | Markus R. Hermann Christofer S. Tautermann Peter Sieger Marc A. Grundl Alexander Weber BIreactive: Expanding the Scope of Reactivity Predictions to Propynamides Pharmaceuticals targeted covalent inhibitors drug discovery covalent warheads reactivity assessment glutathione propynamide |
| title | BIreactive: Expanding the Scope of Reactivity Predictions to Propynamides |
| title_full | BIreactive: Expanding the Scope of Reactivity Predictions to Propynamides |
| title_fullStr | BIreactive: Expanding the Scope of Reactivity Predictions to Propynamides |
| title_full_unstemmed | BIreactive: Expanding the Scope of Reactivity Predictions to Propynamides |
| title_short | BIreactive: Expanding the Scope of Reactivity Predictions to Propynamides |
| title_sort | bireactive expanding the scope of reactivity predictions to propynamides |
| topic | targeted covalent inhibitors drug discovery covalent warheads reactivity assessment glutathione propynamide |
| url | https://www.mdpi.com/1424-8247/16/1/116 |
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