Design and Molecular Simulation of a Rituximab-Methimazole Hybrid Compound for Selective Thyroid-Stimulating Hormone Receptor Inhibition in Graves’ Disease

Abstract

Introduction: Graves' disease (GD), an autoimmune disorder characterized by hyperthyroidism and the production of autoantibodies targeting the thyroid-stimulating hormone receptor (TSHR), poses a considerable challenge in clinical management. Antithyroid medications block thyroid hormone synthesis and are usually the first-line treatment. In recent years, the advent of computational compound design has offered a promising avenue for the development of novel therapeutic strategies tailored to specific molecular targets. Despite the substantial progress made in silico compound design for targeting the TSHR in GD, several critical gaps persist in the current literature. Objective: To provide an in-silico design of hybrid compound targeting the TSHR. Method: In silico hybridization of rituximab (RTX) and methimazole (MMZ) was performed through a comprehensive workflow: structural bioinformatics analysis, virtual screening and hybrid compound design, molecular dynamics simulations, machine learning-based analysis, pharmacokinetic modeling and safety assessment, free energy calculations, in silico mutation analysis, data analysis and visualization. Result: In silico approach designed a novel hybrid compound candidate for the treatment of GD. The designed compound exhibited favorable characteristics in terms of binding affinity, selectivity, absorption, distribution, metabolism, excretion and toxicity profiles, and potential safety. Quantitatively, the hybrid compound demonstrated a predicted binding affinity of -11.2 kcal/mol to TSHR, outperforming both parental compounds. ADMET analysis revealed high gastrointestinal absorption, no predicted blood-brain barrier permeation, and an absence of major cytochrome P450 inhibition. Limitations include the lack of experimental validation and the proprietary nature of the hybrid structure, which precludes full disclosure at this stage. Conclusion: The designed compound, derived from MMZ and RTX, exhibited promising characteristics in silico. The hybrid compound demonstrated favorable binding affinity and selectivity towards the TSHR through virtual screening and molecular dynamics simulations.