Drug Repurposing for Targeting ISL LIM Homeobox 2 in Treatment of Endometriosis: A Computational Study.

Abstract

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.