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QM/MM and molecular dynamics investigation of the mechanism of covalent inhibition of TAK1 kinase.
- Source :
-
Organic & biomolecular chemistry [Org Biomol Chem] 2021 Feb 14; Vol. 19 (6), pp. 1412-1425. Date of Electronic Publication: 2021 Jan 27. - Publication Year :
- 2021
-
Abstract
- TAK1 is a serine/threonine kinase which is involved in the moderation of cell survival and death via the TNFα signalling pathway. It is also implicated in a range of cancer and anti-inflammatory diseases. Drug discovery efforts on this target have focused on both traditional reversible ATP-binding site inhibitors and increasingly popular irreversible covalent binding inhibitors. Irreversible inhibitors can offer benefits in terms of potency, selectivity and PK/PD meaning they are increasingly pursued where the strategy exists. TAK1 kinase differs from the better-known kinase EGFR in that the reactive cysteine nucleophile targeted by electrophilic inhibitors is located towards the back of the ATP binding site, not at its mouth. While a wealth of structural and computational effort has been spent exploring EGFR, only limited studies on TAK1 have been reported. In this work we report the first QM/MM study on TAK1 aiming to better understand aspects of covalent adduct formation. Our goal is to identify the general base in the catalytic reaction, whether the process proceeds via a stepwise or concerted pathway, and how the highly flexible G-loop and A-loop affect the catalytic cysteine located nearby.
Details
- Language :
- English
- ISSN :
- 1477-0539
- Volume :
- 19
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Organic & biomolecular chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 33501482
- Full Text :
- https://doi.org/10.1039/d0ob02273j