Molecular docking study on the DNA binding domain of master regulator of the mammalian HSR protein

Abstract

Heat shock factor 1 (HSF1) is the primary regulator of heat shock response (HSR) in mammalian cancer cells and have been described as a family of transcription factors which are activated with stress conditions. Upon stress, HSF1 upregulates the heat shock proteins (HSP) that help misfolded proteins to refold for the cell functions. One of the heat shock proteins, HSP90, acts as chaperon in cancer cells as well and supports the proliferation and repair of cancer cells. For years, many efforts have been devoted to studies for finding molecules that inhibit these chaperon proteins but at the same time present drug properties, act compatibly with the physiological conditions with the lessened side effects. For this reason, in recent years, drug design studies have mainly concentrated on inhibiting proteins that trigger the process or production of HSP90. As a result of HSF1-HSE complex, formed by HSF1 and the promoter part of DNA, which is called Heat Shock Element, the unwanted heat-shock proteins are synthesized in the cancer cells. HSF1 protein has emerged as a potential target and in recent years shown as a target for specifically breast, pancreas and prostate cancers. In the last decade, in silico drug design has been an integral part of drug development processes. Likewise, in this project, it was planned to design molecules that inhibit HSF1 protein via in silico methods. Herein, our target was to search for inhibitors via in silico methods and bring forward candidate lead molecules to literature. The starting point for the determination of the docking protocol was to calculate the docking scores of the ligands with the most effective IC50 value and to ensure qualitative agreement by comparing the binding energies calculated with the experimental IC50 values. This also enabled us to recognize the residues involved in the binding. The candidate inhibitor structures of the library formed by virtual screening were studied by the receptor (selected flexible residues) - flexible ligand docking procedure. The candidate molecules with the best binding scores were refined by the MM-GBSA method. The molecular dynamic simulation was further performed for nine selected compounds. From the results, we propose candidate lead molecules that can effectively act in cancer cells, especially in breast, pancreas and prostate cancers.