An investigation on the interaction between Hsp90 and p53 in breast cancer: An in-silico approach

Abstract

Breast cancer is a common malignancy and a lifetime risk among females worldwide. Interestingly, it has been observed that Hsp90 is overexpressed in many breast cancer cells. Hsp90 is a highly conserved molecular chaperone and is having ATP dependent functions that involve stress response, homeostatic control, folding, stabilization, activation, and assembly of wide range of client proteins including p53 in various biological processes. Hsp90 inhibition has been reported to be a therapeutic approach in breast cancer.
In the present investigation, Hsp90 and its Hsp complex (Hsp70, Hsp40) has been docked with wild type p53 and mutant p53 with the help of Hex 6.3 docking software. The results showed that while Hsp90 alone has high affinity to bind with wild type p53, its affinity becomes high for mutant p53 when it is associated with multi-chaperone complex. In order to inhibit Hsp90 a wide range of ligands were selected and docked by Hex 6.3 keeping ATP as control. Geldanamyc in having binding energy -315.36 kcal/mol showed highest inhibition among all. The ligplot 1.3.6 analysis confirmed the involvement of four residues Asp93, Phe138, Lys58, and Thr184 at the binding interface. Due to poor solubility and cytotoxicity results, Geldanamycin was modified into ten analogues using Marvinsketch tool 5.9.1 While Analogue 2 found to be the best Hsp90 inhibitor by Hex 6.3 docking, Analogue 9 however observed to be the best when docked by Autodock 4.0 software. Further docking of this inhibitory complex with mutant p53 by Hex 6.3 elucidated the effect of inhibition. Inhibited Hsp90 showed less binding affinity towards mutant p53 depicts the conformational changes upon inhibition.