The successful hybridization of two molecules and the identification of RTX-MMZ through the integrated computational workflow highlight the potential of hybrid molecule design strategies in advancing personalized medicine approaches for treating autoimmune thyroid disorders like GD. This hybrid molecule represents a promising candidate for future pre-clinical and clinical evaluations, offering new avenues for developing targeted and effective treatments in endocrinology.
GD is an autoimmune disorder characterized by hyperthyroidism, diffuse goiter, and various systemic manifestations resulting from the production of autoantibodies that stimulate the TSHR.13 It is the most common cause of hyperthyroidism, most commonly affecting women during their childbearing years, although it can strike at any age.14 The pathophysiology involves the presence of autoantibodies, particularly thyrotropin receptor antibodies (TRAbs), which bind to and activate the TSHR, leading to uncontrolled thyroid hormone synthesis and secretion.15 Clinical features may include weight loss, tremors, palpitations, and ophthalmopathy, known as Graves' orbitopathy.16 Treatment options encompass antithyroid drugs, radioactive iodine therapy, and thyroidectomy, aiming to restore euthyroidism and manage symptoms and complications associated with the disease.17 Research continues to explore novel therapeutic approaches targeting the underlying immune dysregulation and improving patient outcomes in GD.
Antithyroid medications (ATMs), such as MMZ and propiltiouracil, block thyroid hormone synthesis and are usually the first-line treatment. Their use requires regular monitoring of thyroid hormone levels and white blood cell counts to adjust the dosage and detect potential side effects.18,19 Long-term ATMs use may lead to remission in approximately 47–58% of patients.20 RAI therapy involves the administration of radioactive iodine, which is selectively absorbed by thyroid cells and destroys them, leading to a decrease in hormone production. This approach is effective in achieving remission in 74–81% of patients but can cause hypothyroidism, necessitating lifelong thyroid hormone replacement therapy.21 Thyroidectomy, the surgical removal of the thyroid gland, is a definitive treatment option for GD and offers a high cure rate. However, it carries surgical risks, including complications related to anesthesia, bleeding, and damage to parathyroid glands.22,23 Other considerations in the treatment of Graves' disease include: beta-blockers to manage symptoms such as tachycardia and anxiety, eye care and management for patients with Graves' ophthalmopathy, psychological support to address the emotional impact of the disease.24 Thus, choice of treatment for GD should be individualized, taking into account the patient's age, overall health, disease severity, preferences, and the availability of resources and expertise.
Novel therapeutic agents for GD are actively being researched, targeting various aspects of the disease pathophysiology: Monoclonal antibodies targeting the TSH receptor, such as teprotumumab and tocilizumab, have shown promising results in clinical trials, offering potential advantages over conventional ATMs, including a shorter duration of treatment and a lower risk of relapse;25,26 Gene silencing approaches using small interfering RNA (siRNA) to target the TSH receptor are being explored, with early-phase clinical trials demonstrating safety and potential efficacy;27 Thyroid-specific kinase inhibitors that target enzymes involved in thyroid hormone synthesis, such as BRAF and RAF kinases, and have shown promising preclinical results, warranting further clinical investigation.28
RTX is a monoclonal antibody that targets the CD20 B cell receptor, leading to B cell depletion and modulation of the immune system.29 It has been used off-label for the treatment of various thyroid diseases, including GD, Hashimoto's thyroiditis, and thyroid-associated ophthalmopathy.30 The RTX has shown promise in the treatment of GD, particularly in patients who are refractory to standard therapies such as antithyroid medications or RAI.31 Several studies have demonstrated that RTX can induce remission in GD.32 RTX has been shown to be effective in the treatment of thyroid-associated ophthalmopathy, with improvements in both clinical symptoms and proptosis.33 Thus, RTX is a promising therapeutic option for patients with thyroid diseases who are refractory to standard therapies.
In silico studies have explored the potential of molecular hybridization for designing novel molecule candidates with improved potency, selectivity, and reduced side effects.34 However, there are no clinical trials yet involving hybrid molecules for the treatment of Graves' disease. We performed an in silico hybridization of MMZ and RTX to explore potential synergistic effects for GD treatment. The goal was to design a novel hybrid molecule with enhanced potency and selectivity for the thyroperoxidase (TPO) enzyme, which is crucial for thyroid hormone synthesis. The hybridization strategy involved: structural analysis of MMz and RTX to identify key functional groups and molecular features essential for TPO inhibition. Computational docking study to evaluate the binding affinity of various hybrid molecule designs to the TPO enzyme. Molecular dynamics simulations were used to assess the stability and dynamic behavior of the most promising hybrid molecules within the TPO binding site. Free energy calculations to quantify the binding affinity and selectivity of the hybrid molecules for TPO compared to the parent molecule. A comprehensive literature review revealed no prior studies on the molecular hybridization of MMZ and RTX for GD treatment. Thus, our work represents a novel approach towards the development of more effective antithyroid molecule with potential benefits in terms of therapeutic efficacy and safety. Further in vitro and in vivo studies are warranted to validate the predicted synergistic effects of the hybrid molecules and to assess their potential for clinical application in GD.