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Structure-Based Drug Design for Targeting IRE1: An in Silico Approach for Treatment of Cancer
Alireza Poustforoosh1, Sanaz Faramarz2, Mohammad Hadi Nematollahi2,3
1Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
Background:
Endoplasmic Reticulum (ER) stress and Unfolded Protein Response (UPR) play a key role in cancer progression. The aggregation of incorrectly folded proteins in the ER generates ER stress, which in turn activates the UPR as an adaptive mechanism to fix ER proteostasis. Inositol-requiring enzyme 1 (IRE1) is the most evolutionary conserved ER stress sensor, which plays a pro-tumoral role in various cancers. Targeting its' active sites is one of the most practical approaches for the treatment of cancers.
Objective:
In this study, we aimed to use the structure of 4μ8C as a template to produce newly designed compounds as IRE1 inhibitors.
Methods:
Various functional groups were added to the 4μ8C, and their binding affinity to the target sites was assessed by conducting a covalent molecular docking study. The potential of the designed compound for further in vitro and in vivo studies was evaluated using ADMET analysis.
Results:
Based on the obtained results, the addition of hydroxyl groups to 4μ8C enhanced the binding affinity of the designed compound to the target efficiently. Compound 17, which was constructed by the addition of one hydroxyl group to the structure of 4μ8C, can construct a strong covalent bond with Lys907. The outcomes of ADMET analysis indicated that compound 17 could be considered a drug-like molecule.
Conclusion:
Our results revealed that designed compound 17 could inhibit IRE1 activity. Therefore, this designed compound is a remarkable inhibitor of IRE1 and introduces a promising therapeutic strategy for cancer treatment.
Insights
Newly designed compounds targeting Inositol-requiring enzyme 1 (IRE1) show promise for cancer treatment. Compound 17 effectively inhibits IRE1 by forming a covalent bond, suggesting a new therapeutic strategy.
Area of Science:
- Biochemistry
- Molecular Biology
- Medicinal Chemistry
Background:
- Endoplasmic Reticulum (ER) stress and the Unfolded Protein Response (UPR) are implicated in cancer progression.
- Inositol-requiring enzyme 1 (IRE1) is a key sensor of ER stress with a pro-tumoral role.
- Targeting IRE1 active sites offers a therapeutic strategy for cancer treatment.
Purpose of the Study:
- To design novel IRE1 inhibitors using the 4μ8C structure as a template.
- To evaluate the binding affinity and drug-like properties of newly designed compounds.
Main Methods:
- Covalent molecular docking studies were performed to assess binding affinity.
- Functional groups were added to the 4μ8C scaffold.
- ADMET analysis was used to predict in vitro and in vivo potential.
Main Results:
- The addition of hydroxyl groups to 4μ8C improved binding affinity.
- Compound 17 formed a strong covalent bond with Lys907.
- ADMET analysis indicated Compound 17 possesses drug-like properties.
Conclusions:
- Designed Compound 17 effectively inhibits IRE1 activity.
- This compound represents a promising therapeutic candidate for cancer treatment.
- Further in vitro and in vivo studies are warranted.
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