Unveiling the potential of lichen compounds hyaluronic acid conjugates for cervical cancer treatment: a comprehensive in silico analysis.

Abstract

The current study investigated five lichen-derived compounds and their hyaluronic acid (HA) conjugates for activity against five key cervical cancer targets. The lichen compounds and the reference drug topotecan exhibited docking scores ranging from -5.5 to -10.1 kcal/mol and -6.4 to -8.5 kcal/mol, respectively. Notably, the HA-evernic acid conjugate demonstrated the strongest binding to BCL-2 (-10.1 kcal/mol), forming two hydrogen bonds (Ala97, Glu133) and four hydrophobic interactions (Asp100, Arg143, Val145, Tyr199). Similarly, the HA-salazinic acid conjugate displayed high affinity for histone deacetylase 6 (HDAC6; -9.9 kcal/mol). The top-performing compounds, fumarprotocetraric acid, salazinic acid, topotecan, and their HA conjugates, were advanced to computational validation. Pharmacokinetic analysis revealed that HA-salazinic acid (HA-SAL) possessed optimal ADMET properties, including 71.39% human intestinal absorption, no inhibition of cytochrome P450 enzymes or P-glycoprotein, and low toxicity in cardiac (hERG), hepatic, and aquatic models. Density functional theory (DFT) calculations highlighted the HA conjugates of fumarprotocetraric acid (HA-FUM) and salazinic acid as superior to topotecan, with HA-FUM showing the lowest energy gap (-0.1038 eV) and highest softness (19.2678 eV), indicative of enhanced reactivity. Molecular dynamics simulations further validated the stability of HA-salazinic acid-HDAC6 (PDB ID 3PHD) and HA-evernic acid-BCL-2 (PDB ID 4MAN) complexes, outperforming the standard drug hyaluronic acid conjugate. These results underscore the potential of lichen compound-HA conjugates, particularly fumarprotocetraric acid, salazinic acid, and evernic acid, as candidates for cervical cancer therapy. Further preclinical and clinical studies are warranted to evaluate their efficacy and safety for translational applications.