Marine-derived metabolites as effective inhibitors of androgen receptor in prostate cancer: molecular docking and molecular dynamics simulations approach

Abstract

Androgen receptor (AR) signalling plays a crucial role in prostate cancer progression. The main treatment approaches aim either to reduce androgen levels or to block activation of the signalling cascade by androgens. However, therapy often becomes ineffective because mutations in the androgen receptor ligand-binding domain (LBD) can make the receptor constitutively active or less responsive to inhibitors. As a result, prostate cancer may progress to castration-resistant prostate cancer (CRPC). The aim of this study was to identify marine compounds capable of interfering with AR through several domains or regions that are distinct from those targeted by currently approved LBD inhibitors, in order to be effective against resistant forms of prostate cancer. A curated library of marine-derived compounds was created and screened by molecular docking against the AR LBD and DBD, and the most promising candidates were further analysed by molecular dynamics simulations and ADME prediction. Seriniquinone and neoamphimedine had the most favourable binding profiles to both domains with acceptable drug-likeness properties. These results suggest that marine-derived compounds are a potential source of new dual-domain-targeting scaffolds for AR inhibition.