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

Abstract

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.

Heat Shock Protein 90 (HSP90) Inhibitors as Anticancer Medicines: A Review on the Computer-Aided Drug Discovery Approaches over the Past Five Years

“…Hitherto, among the 19 N-terminal targeted HSP90 inhibitors that made it to the clinical trials, none has been approved by FDA. This is because of harmful health effects such as the heat shock response (HSR) induction [ 63 ]. Figure 2 shows 2D structures of some of the failed N-terminal HSP90 inhibitors at the clinical trials.…”

“…Over the years, researchers explored the use of natural products in the development of HSP90 inhibitors. Delmotte and Delmotte-Plaquee discovered radicicol (RD) as an extract from monosporium border and used it as a macrocyclic lactone antibiotic [ 63 , 67 ]. In 1998, Schulte et al identified radicicol as a competitive HSP90 inhibitor to geldanamycin (GA) [ 68 ].…”

“…However, it is like radicicol in mimicking the conformational interactions with aspartate 93 (Asp93). Nevertheless, in vivo studies revealed some loopholes in radicicol's anticancer potency due to its short half-life and fast metabolic reactions [ 63 , 69 ]. Therefore, inhibiting HSP90 with GA has decreased cancerous cells' growth and the breakdown of oncogenic proteins [ 70 ].…”

“…Nevertheless, some already determined experimental structures have been stored and saved in the Protein Data Bank (PDB) [ 106 , 107 ]. Formerly, the investigation of interatomic and intermolecular properties of HSP90 was limited [ 63 ]. Recently, researchers have explored the molecular modelling method in designing three-dimensional models of HSP90, which have provided a substantial understanding of its structural and mechanical dynamic properties [ 108 ].…”

Inhibitors of the Plasmodium falciparum Hsp90 towards Selective Antimalarial Drug Design: The Past, Present and Future

“…This suggests that there are prospects for both radamine and compound 7.7 towards targeting parasite Grp94, which may result in antiplasmodial activity. Preliminary studies identified NVP-AUY922, also known as luminespib ( Figure 7 ), a resorcinylic isoxazole amine that binds and inhibits Hsp90 with a higher affinity than radamide [ 165 ]. The binding affinity for luminesbip to PfGrp94 was 10-fold higher compared to the cytosolic PfHsp90 and HSPC2 [ 81 ].…”