Metformin-Driven Activation of Polymorphic Follicle-Stimulating Hormone Receptors for Polycystic Ovary Syndrome Treatment: A Computational Study.

BACKGROUND Polycystic ovarian syndrome (PCOS) is characterized by anovulation, hyperandrogenism, and, predominantly, insulin resistance. Such characteristics are often associated with disrupted follicle-stimulating hormone receptor (FSHR) function. Conventionally, metformin is commonly used to enhance insulin sensitivity, reduce androgen levels, and indirectly restore FSHR signalling. However, to date, there have been no binding studies investigating metformin-induced FSHR activation and its associated genetic polymorphisms in PCOS. MATERIAL AND METHODS The present study used a systematic approach to examine the structural consequences of wild-type and polymorphic variants of FSHR (A307T and N680S, respectively), along with metformin efficacy, through homology modelling, structural stability analysis, molecular docking, and dynamic simulations. RESULTS The three-dimensional structures of wild-type and variant (A307T and N680S, respectively) FSHR were modelled and validated using computational tools. Pathogenicity prediction revealed that these variants impact the structural stability of FSHR. Molecular docking calculations with metformin showed binding affinities for wild-type (-4.205 kcal/mol), A307T (-4.321 kcal/mol), and N680S (-4.294 kcal/mol). Molecular dynamics (MD) simulations revealed that metformin showed more stable confirmation with A307T and N680S variant forms than wild-type FSHR. These findings suggest that PCOS patients with the A307T and N680S polymorphisms may respond to metformin treatment better than those with wild-type. CONCLUSIONS Our computational findings suggest that PCOS patients with the A307T and N680S polymorphisms may exhibit a better response to metformin treatment than those with the wild-type FSHR, potentially enhancing ovulation activation in insulin-resistant individuals.