Interaction of obtusilactone B and related butanolide lactones with the barrier-to-autointegration factor 1 (BAF1). A computational study
- PMID: 34909681
- PMCID: PMC8663951
- DOI: 10.1016/j.crphar.2021.100059
Interaction of obtusilactone B and related butanolide lactones with the barrier-to-autointegration factor 1 (BAF1). A computational study
Abstract
The barrier-to-autointegration factor 1 (BAF1) protein is a DNA-binding protein implicated in nuclear envelop repair and reformation after mitosis. This nuclear protein is frequently overexpressed in cancer cells and plays a role in the occurrence and development of different tumors. It is a potential therapeutic target for gastric cancer, breast cancer and other malignancies. For this reason, BAF1 inhibitors are searched. The butanolide lactone obtusilactone B (Ob-B) has been found to inhibit VRK1-dependent phosphorylation of BAF1, upon direct binding to the nuclear protein. Taking advantage of the known crystallographic structure of BAF1, we have elaborated molecular models of Ob-B bound to BAF1 to delimit the binding site and binding configuration. The long endoolefinic alkyl side chain of Ob-B extends into a small groove on the protein surface, and the adjacent exomethylene-γ-lactone moiety occupies a pocket comprising to the Ser-4 phosphorylation site of BAF1. Twenty butanolide lactones structurally close to ObB were screened for BAF1 binding. Several natural products with BAF1-binding capacity potentially superior to Ob-B were identified, including mahubanolide, kotomolide B, epilitsenolide D2, and a few other known anticancer plant natural products. Our study provides new ideas to guide the discovery and design of BAF1 inhibitors.
Keywords: BAF1, Barrier-to-Autointegration Factor 1; Barrier-to-autointegration factor 1; Butanolide lactones; Cancer; Ob-B, obtusilactone B; Obtusilactone; VRK1, vaccinia-related kinase 1.
© 2021 The Authors.
Conflict of interest statement
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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References
-
- Bailly C. Anticancer butanolides and lignans from the makko tree, Machilus thunbergii Sieb. & Zucc. Trends Phytochem. Res. 2021;5:136–147.
-
- Bradley C.M., Ronning D.R., Ghirlando R., Craigie R., Dyda F. Structural basis for DNA bridging by barrier-to-autointegration factor. Nat. Struct. Mol. Biol. 2005;12:935–936. - PubMed
-
- Burgess J.T., Cheong C.M., Suraweera A., Sobanski T., Beard S., Dave K., Rose M., Boucher D., Croft L.V., Adams M.N., O'Byrne K., Richard D.J., Bolderson E. Barrier-to-autointegration-factor (Banf1) modulates DNA double-strand break repair pathway choice via regulation of DNA-dependent kinase (DNA-PK) activity. Nucleic Acids Res. 2021;49:3294–3307. - PMC - PubMed
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