Exploratory Covalent Docking of Michael-Acceptor Natural Products at Reactive Cysteines in Cancer Tyrosine Kinases.

ABSTRACT: Tyrosine kinases (TKs) and cyclin-dependent kinases (CDKs) contain reactive cysteines that can be exploited by targeted covalent inhibitors. In this exploratory computational study, we asked whether selected natural-product-like (NP-like) electrophiles bearing Michael-acceptor (MA) motifs could adopt geometries consistent with covalent approaches to these cysteines, in a manner analogous to approved covalent TKIs. Using AutoDockFR with cysteine-centered grids and explicit side-chain flexibility, we performed pocket-focused, within-receptor covalent docking for EGFR, VEGFR2/KDR, PDGFRβ (via PDGFRα surrogate), BTK, CDK7, and CDK12. Reference inhibitors (osimertinib-EGFR, ibrutinib-BTK, THZ1-CDK7, and THZ531-CDK12) reproduced the expected geometries and served as internal controls. NP-like el

SUBMITTER: Lobo F 

PROVIDER: S-EPMC12692623 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature