Understanding the Hsp90 N-Terminal Dynamics: Structural and Molecular Insights into the Therapeutic Activities of Anticancer Inhibitors Radicicol (RD) and Radicicol Derivative (NVP-YUA922)

Heat shock protein 90 (Hsp90) is a crucial component in carcinogenesis and serves as a molecular chaperone that facilitates protein maturation whilst protecting cells against temperature-induced stress. The function of Hsp90 is highly dependent on adenosine triphosphate (ATP) binding to the N-terminal domain of the protein. Thus, inhibition through displacement of ATP by means of competitive binding with a suitable organic molecule is considered an attractive topic in cancer research. Radicicol (RD) and its derivative, resorcinylic isoxazole amine NVP-AUY922 (NVP), have shown promising pharmacodynamics against Hsp90 activity. To date, the underlying binding mechanism of RD and NVP has not yet been investigated. In this study, we provide a comprehensive understanding of the binding mechanism of RD and NVP, from an atomistic perspective. Density functional theory (DFT) calculations enabled the analyses of the compounds’ electronic properties and results obtained proved to be significant in which NVP was predicted to be more favorable with solvation free energy value of −23.3 kcal/mol and highest stability energy of 75.5 kcal/mol for a major atomic delocalization. Molecular dynamic (MD) analysis revealed NVP bound to Hsp90 (NT-NVP) is more stable in comparison to RD (NT-RD). The Hsp90 protein exhibited a greater binding affinity for NT-NVP (−49.4 ± 3.9 kcal/mol) relative to NT-RD (−28.9 ± 4.5 kcal/mol). The key residues influential in this interaction are Gly 97, Asp 93 and Thr 184. These findings provide valuable insights into the Hsp90 dynamics and will serve as a guide for the design of potent novel inhibitors for cancer treatment.