Targeting Hsp27 inhibition in Glioblastoma: A comprehensive in silico investigation.

Glioblastoma (GBM) overexpresses heat shock protein 27 (HSP27), which enhances androgen receptor (AR) transcriptional activity. Inhibiting HSP27 can block AR signaling, offering a potential therapeutic approach for GBM. Computer analysis of structural dynamics showed that lead-optimized COMP2 and COMP3 had enhanced activity compared to COMP1, the positive control and the negative control. The re-docked ligand alignment confirms docking accuracy, while structural analysis shows that compound binding disrupts Hsp27's 3D structure, suggesting inhibition. A critical look at the ligand-bound amino acid behavior suggests slight rigidity relative to the apo, thus suggesting inactivation. Recurring observations suggest that Arg140, Arg136 and His103 are crucial for binding stabilization in the first pocket, whereas when COMP2 migrates to the second pocket, Thr143 appears to be more prominent for binding stabilization. An estimated Gbind of -31.59 ± 6.34 kcal/mol and -33.61 ± 4.09 kcal/mol was obtained for COMP1 and COMP3, respectively, whereas COMP21st and COMP2nd exhibited a Gbind of -21.96 ± 8.16 kcal/mol and -18.36 ± 5.76 kcal/mol, the positive control is -19.60 ± 4.74 and the negative control -8.45 ± 3.23; the reduction in the energy value of COMP2 in the second pocket could be due to shared pocket binding. The study suggests that COMP2 acts as a dual binder, and results from positive and negative controls indicate that the tested compounds could be HSP27 inhibitors. These compounds show promise as drug-like candidates based on pharmacokinetic and physicochemical evaluations. The findings support the development of novel HSP27 inhibitors to effectively block GLM.