HSPB1
September 2023
HSPB1
The heat shock 27 kDa protein 1 (HSP27), also known as HSP beta-1 (HSPB1), is a molecular chaperone protein codified in humans by the HSPB1 gene. HSPB1 has a crucial role in regulating various cellular processes, including apoptosis and protection of cells from damage caused by environmental stress (like heat, oxidative stress, and radiation).
Several reports describe the importance of the chaperone HSPB1 in cancer progression, and various research efforts are focusing on finding compounds that modulate HSPB1 activity. One of the approaches used to develop drugs targeting, this important cancer target, is drug repurposing.
Drug repurposing is a drug discovery strategy where an existing medication for a certain disease is investigated for other therapeutic applications. Since approved drugs are used for repurposing, this approach is usually very convenient since it decreases the risk of safety issues arising in the late steps of drug development. Therefore, it can reduce the costs and time, usually needed for the approval of a novel drug.
In the past, drug repurposing has been mostly done through serendipity, such as the famous example of sildenafil (Viagra), initially developed for heart disease but repurposed for erectile dysfunction. In recent years, several in silico approaches have been used to support drug repurposing studies. Among these, some take advantage of structural data. In fact, the drug's ability to bind to different protein targets is often correlated to the structural similarity of such targets, and so the knowledge of the 3D complex can drive the repurposing effort.
The computational repurposing workflow was based on an interaction-search approach called Protein-Ligand Interaction Profiler (PLIP). PLIP exploits the protein-ligand interaction patterns observed in the experimental 3D structures of the PDB database. These patterns are characteristics of each drug-protein complex and are responsible for the biological effect observed. Compounds that form similar interaction patterns might interact with the same proteins and, therefore, have the same therapeutical activity.
The starting point of this drug repurposing effort was brivudine (BVDU, Image 1A), targeting several kinases. The binding of BVDU to HSPB1 was also proven by affinity chromatography suggesting its anticancer activity. Due to the lack of BVDU crystal structures in a complex with the anticancer target HSPB1, Salentin et al. used the structural information of 3D crystal BVDU in a complex with several kinases, analyzing the protein-ligand interaction network. Some of the characteristics interactions of these complexes are (Image 1B):
the pi-stacking formed by the nucleobase
halogen bond formed by the bromovinyl moiety
Image 1: A) Brivudine 2D chemical structure, B) 3D structure of the Brivudine-kinase complex (PDB: 2VQS).
The interactions selected as a starting point for the search are aromatic interaction between nucleobase of BVDU and the phenylalanine and halogen bond between bromovinyl moiety and serine (interactions are indicated with blue arrows).
They hypothesized that if FDA-approved drugs share interaction patterns with BVDU, they might also bind to the same target protein in cancer and thus, have anti-cancer activity.
Using the interaction pattern of BVDU as a query of their search, they screened the structures deposited in the PDB database. Among their results, 12 structures were in complex with an FDA-approved ligand, and half showed a different chemical scaffold to brivudine.
The authors focused the experimental validation on the anti-malaria drug amodiaquine (Image 2). This drug interacts with the target Histamine N-methyl transferase (HNMT) with a pattern of interaction similar to brivudine: both the halogen and aromatic bond observed in the brivudine-kinase complex are present also in the amodiaquine-HNMT structure.
Image 2: A) Amodiaquine 2D chemical structure; B) comparison of the binding mode of Brivudine and Amodiaquine.
The interaction pattern including both the halogen and aromatic bond observed in the brivudine-kinase complex (PDB: 2VQS) are present in the amodiaquine-HNMT structure (PDB: 2AOU) (interactions are indicated with blue arrows). The superposition was done with the 3decision software.
This structural similarity translated into a similar biological activity. In fact, in vitro experiments showed that amodiaquine has the same anti-cancer effect observed with brivudine, suppressing the growth of cancer cells. Also, a biochemical assay confirmed that both drugs inhibit the same cancer target, the heat shock protein HSPB1, and that amodiaquine is 43 times more potent than BVDU.
This study is a clear example of the use of structural data by exploiting similarities between complexes to successfully contribute to the repurposing of drugs.
BONUS
We reproduced the use case illustrated in this paper with 3decision’s Interaction Search feature. Starting from Brivudine, we were able to identify Amodiaquine as a ligand with similar interactions, replicating the finding of the paper and thus validating our method. In addition, we identified other FDA-approved ligands having different scaffolds but maintaining similar interaction patterns as BVDU.
Reference:
Salentin, S., Adasme, M.F., Heinrich, J.C. et al. From malaria to cancer: Computational drug repositioning of amodiaquine using PLIP interaction patterns. Sci Rep 7, 11401 (2017). https://doi.org/10.1038/s41598-017-11924-4