Structure-Based Discovery of Immunomodulators for Stunting Inspired by Caulerpin: A Rational Approach Targeting Immune Homeostasis

Stunting remains a critical public health issue, affecting millions globally and hundreds of thousands in Indonesia annually, thus demanding innovative interventions. While immune dysfunction is implicated in the pathogenesis of stunting, it is often underemphasized in therapeutic strategies. This study leverages structure-based drug design and similarity searching to identify novel immunomodulators with potential application in stunting treatment. Initial molecular docking revealed that caulerpin (1), an algal alkaloid, exhibited promising binding to immune-related targets. However, its suboptimal drug-likeness prompted the use of SwissSimilarity structural search, leading to the identification of CPG- 52852 (7), a TLR7 agonist. Compound 7 demonstrated strong predicted immunomodulatory properties via PASS analysis. Further similarity searching, using 7 as a query, identified imiquimod (8) and resiquimod (9), sharing similar imidazoquinolinone scaffold with 7. Building upon the scaffold, de novo design of R848 with Metatox generated ten novel compounds (12-21) with predicted immunomodulatory activity nearly equal or improved drug-likeness with ADMET score of 0.25, 0.28, 0.28, and 0.32 for compounds 13, 14, 15, and 17 compared to 0.29 for their parent molecule, R848. Unlike the TLR-7/8 agonist R848, compounds 13, 14, 15, and 17 preferentially interacted with amino acid residues unrelated to the ones reported for the TLR-7/8 agonist, suggesting a distinct mechanism of action (e.g., antagonism or allosteric modulation). These allosteric modulators represent promising leads for treating immune dysfunction-related diseases, including stunting, where alternative mechanisms beyond direct agonism are needed.