In silico profiling of the ADMET properties and inhibitory potentials of alkaloids against IFIT5 in renal cell carcinoma

Abstract

Alkaloids from diverse classes have demonstrated efficacy in anticancer treatments. Interferon-induced protein with tetratricopeptide repeats 5 (IFIT5) is implicated in the pathogenesis of renal cell carcinoma (RCC). Less is known about the inhibitory effects of these pharmacologically relevant classes of alkaloids on IFIT5. Thus, we determined the ADMET properties of these alkaloids, as well as their inhibitory potentials on IFIT5. Fifty alkaloids were retrieved from PubChem. The structure of IFIT5 was obtained from Protein Data Bank and processed using Biovia Discovery Studio to eliminate nonstandard molecules. Molecular docking was performed using PyRx to assess the binding affinities of protein-ligand complexes, while ADMET analysis was conducted using AdmetSAR and swissADME. Docking results revealed that all 50 selected alkaloids demonstrated high IFIT5 binding effects, ranging from -7.1 to -11.0 kcal/mol, surpassing the di(hydroxyethyl)ether cocrystallized ligand (-3.9 kcal/mol), with nortopsentin A emerging as the most promising hit. Additionally, four of the top five IFIT5 binding alkaloids (nortopsentin A, stylopine, oxymatrine, and deoxytubulosine) displayed favourable drug-like properties. The propitious drug-like properties and strong IFIT5 binding impacts displayed by these alkaloids, particularly nortopsentin A underscore their potential for advancement into pre-clinical/clinical trials for developing selective IFIT5 inhibitors for targeted RCC treatment.