Exploring the mechanism of stigmasterol against androgenetic alopecia using geometry optimization, network pharmacology, molecular docking, and molecular dynamics studies.

Androgenetic alopecia (AA) is a common condition that is characterized by androgen-induced follicular miniaturization and abnormal hair cycling, against which there are as yet no effective therapeutic interventions. The current study outlines the possibility of using stigmasterol (STR) as a therapeutic agent of AA, using geometry optimization, network pharmacology, molecular docking, and molecular dynamics (MD) simulations. Geometry optimization was done using the PM3 Hartree-Fock protocol, and the most stable conformation of STR was found with a total electronic energy of -164.36 au. The integrative gap analysis of target interactions presented sixty-three common genes in the target interaction between STR pharmacodynamics and AA pathogenesis. Ten core genes (AR, CDK4, ESR1, ESR2, HIF1A, MAPK3, MDM2, NR3C1, PGR, PPARG) were subsequently chosen in order to highlight the mechanistic nature of AA. Specifically, AR mediates androgenic signaling, which triggers the follicular miniaturization; ESR1 and ESR2 affect the cutaneous hair cycling and inflammatory cascades, and MAPK3 coordinates the inflammatory and apoptotic pathways. Docking studies revealed a strong binding of STR with all the hub genes, with the strongest binding affinity against MAPK3 (-9.1 kcal/mol) being observed compared to the binding energy of finasteride (-8.6 kcal/mol). Evidence of the thermodynamic stability of the STR-MAPK3 complex was found by MD simulations over 200 nanoseconds. Taken together, these results support the ability of STR to regulate a variety of AA-related mechanisms and thus predetermine it as one of the most promising natural therapeutic agents. However, further empirical confirmation is mandatory to unify the prospective application of STR in the clinical treatment of AA.