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

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 inhibi-tory 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 viola-tions 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 cheli-donine 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.