Design of novel Geldanamycin analogue hsp90 alpha-inhibitor in silico for breast cancer therapy

Abstract

Background: Geldanamycin, which is one of the most potent and effective hsp90 alpha inhibitor until date, is normally used to target breast cancer. Inhibition of hsp90 alpha leads to the degradation of client proteins involved in the initiation and progress of breast cancer pathogenesis. Hence, Geldanamycin has been widely pursued as a treatment option for breast cancer. However, it failed to move into the clinics due to the toxicity associated with its solubility. Geldanamycin was modified chemically to develop 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) and later 17-Dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), which have higher solubility and lesser toxicity. Nonetheless, in order to achieve highest efficacy against breast cancer, a more potent, soluble and least toxic hsp90 alpha inhibitors need to be developed.

Hypothesis: We hypothesize that designing a novel Geldanamycin analogue with increased affinity and efficacy would provide a probability of having less toxic effect in the therapy of breast cancer. We also hypothesize that hsp90 alpha forms a multi-chaperone complex with hsp70 and hsp40 and thus assist the folding and maturation of number of client proteins including cellular p53. We further hypothesize that the higher binding affinity of the novel Geldanamycin analogue for hsp90 alpha triggers the degradation of nonfunctional mutant p53 by cellular proteasomes.

Experimental design: Ten different Geldanamycin analogues were designed using Marvinsketch software. Binding affinity of hsp90 alpha and its complex (hsp70, hsp40) with wild type p53 and mutant p53 were determined using Hex 6.3. Binding affinities of ten different analogues for hsp90 alpha were determined by estimating binding energies of molecules using Hex 6.3 and Autodock 4.0 softwares.

Results: The estimation of molecular docking energies using Hex 6.3 and Autodock 4.0 software proved that Analogue 9 was the best hsp90 alpha inhibitor among all ten analogues designed and the existing inhibitors. Following hsp90 alpha inhibition using Analogue 9 and subsequent docking results using Hex 6.3 software showed less binding affinity of Analogue 9 for mutant p53 than the wild version, suggesting the increased chance of the degradation of mutant p53 by cellular machines.

Conclusions: Based on our findings, we propose Analogue 9 to be the more efficient hsp90 alpha inhibitor than existing inhibitors. Furthermore, the chemical synthesis of Analogue 9 at the laboratory scale and successful in vitro and in vivo studies in breast cancer model would lead the compound into the clinical stage.