In silico dissection of FLG mutations and therapeutic potential of Solanum nigrum Phytocompounds against ichthyosis vulgaris: an integrated computational pharmacology and molecular docking approach

Ichthyosis vulgaris (IV) is a common monogenic skin disorder, mainly caused by loss-of-function mutations in the filaggrin ( FLG ) gene. This results in impaired skin hydration and barrier function. We identified deleterious nsSNPs in FLG using 11 bioinformatics predictors, with F15L, F15S, and L33P identified as the most pathogenic. Wild-type and mutant FLG structures were modeled; 22 phytochemicals from Solanum nigrum were evaluated through molecular docking (Maestro 12.5), molecular dynamics (100 ns), and MM-PBSA binding free energy calculations. Additionally, density functional theory (DFT) was employed to compute electronic properties of lead ligands. Docking analysis revealed that SN-10 (−5.1 kcal/mol) and SN-20 (−4.2 kcal/mol) had stronger binding affinities than other screened compounds. These compounds formed stable hydrogen bonds with HIS59, LYS79, and LEU75, as well as hydrophobic contacts with PHE56 and MET76. MD simulations confirmed the conformational stability of these complexes, as evident from stable hydrogen-bond profiles and consistent RMSD values. MM-PBSA free energy calculations further supported the strong binding potential of SN-10 with the FLG protein. DFT-derived quantum descriptors, such as the HOMO–LUMO gap, ionization potential, and electronegativity, indicated favorable electronic properties and reactivity of these phytocompounds. SN-10 and SN-20 are particularly promising small-molecule stabilizers. They are prioritized in this integrative computational framework for identifying deleterious FLG mutations and S. nigrum phytochemicals. These findings provide a theoretical foundation for future experimental validation and the development of phytotherapeutic interventions in ichthyosis vulgaris