Aframomum melegueta (grains of paradise) compounds inhibit carbonic anhydrase XII in brain cancer: An in silico approach

Carbonic anhydrase XII (CA) has emerged as a critical therapeutic target in brain cancer, particularly glioma, which is characterized by rapid proliferation, a highly invasive nature, and resistance to therapy. Aframomum melegueta (grains of paradise) is a medicinal plant whose bioactive compounds are reported to possess anticancer properties. This study investigates the inhibitory potentials of these phytocompounds on CA using an in silico approach. The molecular docking of 141 A. melegueta bioactive compounds, along with standard carbonic anhydrase inhibitors (SCAI; acetazolamide and SLC-0111), was performed using the Schrödinger suite. Induced-fit docking; molecular mechanics with generalized Born and surface area solvation (MMGBSA); absorption, distribution, metabolism, and excretion; and automated quantitative structure–activity relationship analyses of the hit compounds were performed. The binding affinity of 1-(3,4-dihydroxy-5-methoxyphenyl)-7-(3,4-dihydroxyphenyl)heptane-3,5-diyldiacetate (−10.230 kcal/mol) and 1,7-bis(3,4-dihydroxy-5-methoxyphenyl)heptane-3,5-diyldiacetate (−8.564 kcal/mol) with CA was better compared to acetazolamide (−5.225 kcal/mol) and SLC-0111 (−3.792 kcal/mol). Amino acids VAL 125, VAL 147, LEU 203, and TRP 214 play crucial roles in stabilizing the compounds. The induced-fit docking score of 1-(3,4-dihydroxy-5-methoxyphenyl)-7-(3,4-dihydroxyphenyl)heptane-3,5-diyldiacetate (−579.84 kcal/mol) and 1,7-bis(3,4-dihydroxy-5-methoxyphenyl)heptane-3,5-diyldiacetate (−576.49 kcal/mol) were better than the SCAIs. The MMGBSA analysis showed that the binding complexes of the hit compounds were stable, and their pharmacotoxicity profiles complied with Lipinski’s rule of druggability. The predicted pIC50 of 1-(3,4-dihydroxy-5-methoxyphenyl)-7-(3,4-dihydroxyphenyl)heptane-3,5-diyldiacetate (4.9607) was higher than that of acetazolamide (4.3003) and SLC-0111 (4.7022), suggesting greater potency at minimum concentration. Molecular dynamics simulation at 200 ns further validated the inhibitory potential of 1-(3,4-dihydroxy-5-methoxyphenyl)- 7-(3,4-dihydroxyphenyl)heptane-3,5-diyldiacetate (−10.230 kcal/mol) and 1,7-bis(3,4-dihydroxy-5-methoxyphenyl)heptane-3,5-diyldiacetate (−8.564 kcal/ mol). The findings suggest that these A. melegueta hit compounds are strong CA inhibitors and can be used to develop novel therapeutic agents for treating brain cancer.