Discovery of novel peptidomimetics against HSP90-HOP interactions towards improved cancer therapeutics using machine...

The HSP90-HOP interaction orchestrates transfer of client proteins from HSP70 to HSP90, promoting their conformational maturation and stabilisation and thereby sustaining oncogenic signalling. The study explores a promising alternative for cancer chemotherapy by targeting this interface rather than the traditional ATP-binding site, which may circumvent the toxicity associated with classical HSP90 inhibitors. Despite its therapeutic relevance, the HSP90-HOP interface remains underexplored, particularly in the context of structure-guided peptidomimetic inhibitors, highlighting a critical gap in strategies to modulate proteostasis in cancer.

This study sought to identify a promising peptidomimetic molecule capable of disrupting the HSP90-HOP interface.

A seven-residue template peptide was engineered from a crucial segment of HOP, with hotspot residues identified through in silico mutagenesis. These residues were subsequently employed to retrieve a library of 200 peptidomimetic molecules. An in-house developed classification-based machine learning model served as the primary screening tool to identify potential HSP90-HOP interaction modulators. The shortlisted compounds were subsequently evaluated by molecular docking, binding free energy estimation, machine learning-assisted scoring, and ADMET profiling to ensure structural stability, binding reliability, and pharmacokinetic suitability. This scrutiny resulted in the selection of five lead compounds, with MMs01053537 emerging as a top candidate.

The ML model achieved an accuracy of 0.9055 and an ROC-AUC of 0.9537, indicating strong predictive performance of the model. The lead molecule MMs01053537 demonstrated a favourable binding score of -85.92 kcal/mol, along with a robust stability profile during molecular dynamics simulations. To further assess the consistency of the predicted binding mode across trajectory-derived conformations, ensemble docking and MD-enhanced binding free-energy analysis, along with statistical evaluation were performed.

Collectively, these findings position MMs01053537 as a potential candidate for disrupting the HSP90-HOP interaction. However, experimental validation remains essential to confirm its therapeutic potential and support further biological evaluation of the compound.