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.

Proteomics Studies Suggest That Nitric Oxide Donor Furoxans Inhibit In Vitro Vascular Smooth Muscle Cell Proliferation by Nitric Oxide-Independent Mechanisms

“…Despite its upregulation is often associated with cancer development and cancer cell proliferation and migration [125,126], in in vivo SMCs, BANF1 upregulation might increase resistance to vessel mechanical stress by playing a critical role in nuclear rupture repair [127]. Transient nuclear envelope ruptures can lead to DNA damage, which is directly related to aging and, eventually, to apoptosis.…”