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Published on: December 11, 2016
Drug Repurposing for Targeting ISL LIM Homeobox 2 in Treatment of Endometriosis: A Computational Study
Soodeh Mahdian1, Raha Favaedi1, Gelareh Mikaeeli1,2
1Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran.
Background:
Endometriosis is a prevalent women's health disorder that lacks a definitive cure. Numerous studies have been conducted to identify the underlying causes of this disease and select the most effective pharmaceutical intervention. ISL LIM homeobox 2 (ISL2) plays a significant role in promoting angiogenesis. Contemporary investigations strongly suggest that inhibiting angiogenesis could lead to the modulation of endometriosis and reduce associated symptoms. This study aims to repurpose drugs to target ISL2 for endometriosis treatment.
Materials And Methods:
In this computational study, we sought to confirm that ISL2 is an appropriate target for this study by evaluating its expression in the endometrial tissues of patients diagnosed with endometriosis, as well as in tissues from a control group of healthy women. Subsequently, we used computational techniques to select the best inhibitor for ISL2 from among select food and drug administration (FDA)-approved drugs.
Results:
There was a significant increase ISL2 gene expression in the tissues of women with endometriosis. Therefore, we selected the ISL2 protein as a target for drug repurposing. Initial docking results revealed that, out of 2471 FDAapproved drugs, six (Dactinomycin, Paritaprevir, Ivermectin, Ergotamine, Alectinib, and Simeprevir) exhibited the most favourable binding energy (ΔG ≤-8 kcal/mol) with ISL2. Molecular dynamics (MD) simulations of these six complexes showed that Ivermectin displayed the lowest root mean square fluctuation (RMSF) and root mean square deviation (RMSD), as well as the highest count of hydrogen bonds and number of contacts, which indicated a more stable formation of this complex with ISL2.
Conclusion:
Although these six drugs appear to be promising candidates for modulating endometriosis, Ivermectin is more likely to effectively inhibit ISL2.
Insights
This study identified ISL2 as a potential drug target for endometriosis by repurposing FDA-approved drugs. Ivermectin showed the most promise for inhibiting ISL2 and treating endometriosis.
Area of Science:
- Reproductive medicine
- Computational drug discovery
Background:
- Endometriosis is a common condition without a cure.
- ISL LIM homeobox 2 (ISL2) promotes angiogenesis, a process implicated in endometriosis.
- Inhibiting angiogenesis may help manage endometriosis symptoms.
Purpose of the Study:
- To repurpose drugs to target ISL2 for endometriosis treatment.
- To evaluate ISL2 as a therapeutic target for endometriosis.
Main Methods:
- Computational analysis of ISL2 gene expression in endometriosis tissues versus controls.
- In silico screening of FDA-approved drugs for ISL2 inhibition.
- Molecular docking and dynamics simulations to assess drug-target interactions.
Main Results:
- Significantly higher ISL2 expression was observed in endometriosis tissues.
- Six FDA-approved drugs showed favorable binding to ISL2.
- Ivermectin demonstrated the most stable interaction with ISL2.
Conclusions:
- ISL2 is a viable drug target for endometriosis.
- Ivermectin is a promising candidate for further investigation in endometriosis treatment.
