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Molecular Docking Investigation of Inhibitors of the Heat Shock Protein 90

posted Dec 30, 2015, 4:41 AM by Emilio Gallicchio   [ updated May 12, 2016, 3:33 PM ]

by Godfrey Rollins
as part of the CHEM 5130 Independent Research course at the Department of Chemistry at Brooklyn College, Fall 2015.


HSP90 is a heat shock protein that plays an important role in our bodies by causing them to function properly. This role includes assisting in correct protein folding as well as stabilizing them when they are exposed to high temperatures. However, cancerous cells rely on the protein for growth and survival. In addition to that, these cells produce more of this protein than their healthy counterparts. Inhibition of this protein makes it easier for the cancer cells to be destroyed. Several HSP90 inhibitors were discovered and synthesized and are tested against this protein. As there are few crystal structures of the inhibitors present, more structures need to be predicted in order to have a better on how these inhibitors alter their structure and bind to HSP90. In this project, we use computational docking methods in order to predict what these structures of the complexes the inhibitors form when they bind to HSP90.


We first start off by obtaining a structure of an HSP90 inhibitor. We check it to see that the atoms are correct and that the formal charge of the inhibitor is 0. In this example, we use BIIB021.


Secondly, we prepare possible structures of the inhibitor using LigPrep. This results in various protonation states and possible tautomers. Here, we see a protonated N atom on the left aromatic ring on BIIB021.


Thirdly, we create a receptor grid of a known crystal structure we obtained. In this example we will dock BIIB021 onto a receptor grid obtained from the crystal structure with PDB ID code: 4B7P This code consists of another inhibitor, NMS-E973 bound to HSP90. The receptor grid showing the binding site is seen below.


Finally, we dock our inhibitor onto the receptor grid.


From what we see here, BIIB021 in its protonated state forms a hydrogen bond with Aspartic Acid and a halogen bond with Lysine. This is one of the possible structures of BIIB021 when it binds to HSP90. As several of these inhibitors have different structures, there are different possible complex structures that can be predicted.

2D Structures of the inhibitors used in this study are available in the PDF file below. FP IC50 values are expressed in µM.

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Godfrey Rollins,
Dec 30, 2015, 1:20 PM
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Godfrey Rollins,
Dec 30, 2015, 2:09 PM
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