Lobaric Acid

Lichen-derived compounds have demonstrated promising anti-cancer potential, attributed to their bioavailability and unique structural properties. This study evaluates the therapeutic efficacy of five lichen compounds-fumarprotocetraric acid, salazinic acid, evernic acid, sekikaic acid, and lobaric acid-against cervical cancer, using molecular docking, density functional theory (DFT), and molecular dynamics (MD) simulations. Drug-likeness validation confirmed that evernic acid, topotecan, and ifosfamide adhere to Lipinski's rule of five. Molecular docking against ten cervical cancer target proteins revealed high binding affinities, with fumarprotocetraric acid (- 10.4 kcal/mol against 1KTZ), salazinic acid (- 10.9 kcal/mol against 2PVF), and evernic acid (- 11.3 kcal/mol against 2BIM) outperforming standard drugs such as topotecan (- 10.2 kcal/mol against 2BIM). ADME (Absorption, Distribution, Metabolism, and Excretion) profiling confirmed favorable pharmacokinetics, with salazinic acid exhibiting the highest human intestinal absorption (89.35%). Bioactivity analysis further supported enhanced activity for lichen compounds (0.0-5.0) compared to standard drugs (- 5.0-0.0). DFT analysis demonstrated lower energy gaps for fumarprotocetraric acid (- 0.1806 eV) and salazinic acid (- 0.1632 eV), indicating high chemical reactivity. MD simulations confirmed greater stability of lichen-protein complexes over anti-cancer drugs, with the 2BIM-evernic acid complex displaying the highest Molecular Mechanics Generalized Born Surface Area (MMGBSA) binding energy (- 114.29 kcal/mol). These findings highlight the therapeutic potential of fumarprotocetraric acid, salazinic acid, and evernic acid, warranting further preclinical investigations to establish their efficacy against cervical cancer.

Protein tyrosine phosphatase 1B plays a significant role in type 2 diabetes mellitus and other diseases and is therefore considered a new drug target. Within this study, an acetone extract from the lichen Stereocaulon evolutum was identified to possess strong protein tyrosine phosphatase 1B inhibition in a cell-free assay (IC50 of 11.8 µg/mL). Fractionation of this bioactive extract led to the isolation of seven known molecules belonging to the depsidones and the related diphenylethers and one new natural product, i.e., 3-butyl-3,7-dihydroxy-5-methoxy-1(3H)-isobenzofurane. The isolated compounds were evaluated for their inhibition of protein tyrosine phosphatase 1B. Two depsidones, lobaric acid and norlobaric acid, and the diphenylether anhydrosakisacaulon A potently inhibited protein tyrosine phosphatase 1B with IC50 values of 12.9, 15.1, and 16.1 µM, respectively, which is in the range of the protein tyrosine phosphatase 1B inhibitory activity of the positive control ursolic acid (IC50 of 14.4 µM). Molecular simulations performed on the eight compounds showed that i) a contact between the molecule and the four main regions of the protein is required for inhibitory activity, ii) the relative rigidity of the depsidones lobaric acid and norlobaric acid and the reactivity related to hydrogen bond donors or acceptors, which interact with protein tyrosine phosphatase 1B key amino acids, are involved in the bioactivity on protein tyrosine phosphatase 1B, iii) the cycle opening observed for diphenylethers decreased the inhibition, except for anhydrosakisacaulon A where its double bond on C-8 offsets this loss of activity, iv) the function present at C-8 is a determinant for the inhibitory effect on protein tyrosine phosphatase 1B, and v) the more hydrogen bonds with Arg221 there are, the more anchorage is favored.