Exploring the pharmacokinetic properties and inhibitory potentials of plant-derived alkaloids against nuclear protein targets in triple-negative breast cancer: An In Silico approach

Abstract

Triple-negative breast cancer (TNBC) overexpresses poly-ADP ribose-polymerase (PARP), and histone deacetylase (HDAC) specific isoforms, PARP2 and HDAC7 respectively. There is a paucity of research assessing plant-based alkaloids for the development of HDAC7- and PARP2-isoform specific inhibitor compounds. This study evaluated the pharmacokinetic properties and inhibitory potentials of plant-derived alkaloids, including chelidonine and oxymatrine on PARP2 and HDAC7 using in silico protocols. ADME/T analysis revealed that chelidonine and oxymatrine had high human intestinal absorption and blood-brain barrier permeability, low CYP promiscuity, and no Ames mutagenicity or carcinogenicity. Moreso, chelidonine and oxymatrine had zero violations of the Lipinski rule of five. Chelidonine displayed the greatest PARP2 binding affinity (-9.6 Kcal/mol), when compared to oxymatrine (-8.4 Kcal/mol), co-crystalized ligand (-7.9 Kcal/mol) and the reference veliparib drug (-8.8 Kcal/mol). However, the co-crystalized HDAC-IN-5 had the most favorable binding interaction with HDAC7 (-9.8 Kcal/mol). The binding impact of chelidonine on HDAC7 (-8.6 Kcal/mol) was also greater than that of oxymatrine (-7.3 Kcal/mol) and romidepsin (-7.7 Kcal/mol). Chelidonine exhibited propitious drug-like properties and stronger inhibitory effects on PARP2 and HDAC7 than the reference drugs. This indicates its suitability for progression into pre-clinical and clinical trials for the development of PARP2- and HDAC7-isoform specific inhibitors that could be used for targeted TNBC treatment. © 2023