Identification of GPI-Anchored Wall Transfer Protein 1 Modulators for Fungal Infections Through Generative AI and Physics-Based Approaches

Glycosylphosphatidylinositol (GPI) anchored wall transfer protein 1 (GWT1), a fungal-specific inositol acyltransferase, catalyzes the palmitoylation of GlcN-PI in GPI-anchor biosynthesis, crucial for mannoprotein trafficking and attachment, which are vital for cell wall integrity, biofilm formation, and virulence. More than 60,000 AI-generated molecules produced using REINVENT4 were screened using ADMET-AI and GNINA. DeepSA and PharmacoNet were used to select synthesizable and pharmacophorically rich molecules. The dynamic behaviour was explored using molecular dynamics (MD). Finally, molecular reactivity was assessed using density functional theory (DFT). After ADMET filtering, 6190 compounds were docked against GWT1, of which 315 showed better predicted binding energies than the co-crystal ligand. DeepSA identified 105 readily synthesizable candidates, and PharmacoNet retained 32 compounds with favourable pharmacophoric features, from which four final candidates (AF_M1, AF_M2, AF_M3, and AF_M4) were prioritized for further analysis. MD simulation suggested stable binding behavior towards GWT1. DFT analysis indicated favourable electronic properties, low HOMO-LUMO energy gaps, and stable optimized geometries. These molecules could serve as promising lead candidates and potential new therapeutic agents for invasive fungal infections, pending validation.