Design and development of novel peptidomimetic compounds for cancer therapeutics: Focus on HSP90–CDC37 interaction

Abstract

Background: The HSP90 and CDC37 molecular chaperone complex governs the stability and function of numerous client protein kinases, making it a crucial cancer target. Given their central role, disrupting this interaction induces proteotoxic stress and inhibits tumor progression. Therapeutic peptides are the mainstay of treatment for disruption of key interactions, yet they face limitations such as toxicity, resistance, and poor stability. Aim: This study aims to leverage peptidomimetics as novel disruptors of the HSP90–CDC37 interaction. Methods: Two peptides, a 9-mer and a 7-mer, were rationally designed by analyzing key regions facilitating HSP90–CDC37 complex formation. In silico mutational analysis identified crucial residues essential for interaction and ultimately supported the retrieval of peptidomimetic compounds. Molecular docking and binding free energy analysis were employed to explore the affinity of the mimetics for HSP90. The ADMET screening ensured drug-like properties of the compounds. Results: Among the tested compounds, MMs02350546 emerged as the most promising, maintaining strong interactions with the critical Glu47 residue, disrupting ATPase activity, and destabilizing oncogenic proteins. Molecular dynamics simulations provided insight into the atomic-level fluctuations upon ligand binding and confirmed the favorable positioning of the molecule in the binding pocket of HSP90. Conclusion: Collectively, the findings highlight MMs02350546 as a potential disruptor of HSP90–CDC37 interaction, presenting a promising therapeutic strategy against cancer via chaperone complex destabilization. The molecular feature, particularly the presence of the triazole moiety in the mimetic, is hypothesized to play a pivotal role in the compound’s bioactivity. This study may further pave the way toward preclinical evaluation of peptidomimetics as a novel modulator of oncogenic protein stability.