Development of highly predictive 3D-QSAR CoMSIA models for anthraquinone and acridone derivatives as telomerase inhibitors targeting G-quadruplex DNA telomere

G-quadruplex structures of DNA represent a potentially useful target for anticancer drugs. Telomerase enzyme, involved in immortalization of cancer cells is inhibited by stabilization of G-quadruplex at the ends of chromosomes. Anthraquinone and acridone derivatives are promising G-quadruplex ligands as telomerase inhibitors. So far, optimization of these ligands remained hampered due to the lack of creditable quantitative structure–activity relationships. To understand the structural basis of anthraquinone and acridone derivatives, a predictive 3D-QSAR model has been developed for the first time for telomerase inhibitory activity of G4 ligands, employing comparative molecular similarity indices analysis (CoMSIA). Considering the proposition that the basic nitrogens in these compounds should exist in protonated form at physiological pH the protonated forms of the reported compounds were analyzed and investigated. The QSAR model from conformational template Conf1 exhibited best correlative and predictive properties. The actual predictive abilities of the QSAR model were thoroughly validated through an external validation test set of compounds. The statistics indicate a significantly high prediction power of the best model (r2, 0.721), supporting the proposed molecular mechanism of DNA G-quadruplex ligands.

Graphical abstractFigure optionsDownload full-size imageDownload high-quality image (128 K)Download as PowerPoint slideResearch highlights▶ Hydrophobicity of ligands favors G-quadruplex stabilization. ▶ H-bond acceptor and donor fields of ligands favor G-quadruplex stabilization. ▶ Conformational search-based alignment results into highly predictive CoMSIA model. ▶ Protonation of ligands is an important factor for G-quadruplex stabilization.