PHARMACOLOGICAL AND TOXICOLOGICAL ASSESSMENT OF TWO MEDICINALLY POTENT COMPOUNDS (PROLYLLEUCINE AND UROCANIC ACID) ISOLATED FROM MAIZE KERNELS CULTIVATED IN KALIACHAK, MALDA (W. BENGAL), INDIA

Md Yousuf Alam, Sudipta Kumar Sil*

Pairing target-receptor molecular docking with early-stage ADMET screening offers a robust framework for filtering out weak drug candidates before expensive clinical development begins. This study used the SwissADME and ProTox 3.0 platforms to run a detailed computational evaluation of the pharmacokinetic properties, structural drug-likeness, and toxicological profiles of two distinct bioactives: urocanic acid (138.12 g/mol) and a protected prolylleucine derivative (362.40 g/mol). Computational modeling via the BOILED-EGG diagram mapped both metabolites securely within the high passive intestinal absorption zone, indicating high oral bioavailability alongside a minimal risk of central nervous system exposure due to their inability to cross the blood-brain barrier. However, clear differences emerged regarding active transport and molecular architecture. While urocanic acid behaves as a P-glycoprotein non-substrate (PGP-), prolylleucine acts as a P-gp substrate (PGP+), leaving it vulnerable to cellular efflux. Furthermore, the bioavailability radar flagged the prolylleucine compound for excessive molecular flexibility. This conformational freedom introduces an entropic penalty during target binding, even though the compound complies with Lipinski's Rule of Five. Safety analysis via ProTox 3.0 revealed pronounced liabilities for the prolylleucine scaffold, most notably a striking near-100% probability of interacting with Cytochrome P450 2E1 (CYP2E1), signaling a high risk of metabolic bioactivation and subsequent hepatotoxicity. Moreover, the compound showed high binding affinity toward endocrine hubs, including aromatase, estrogen receptor alpha, and the androgen receptor ligand-binding domain. Ultimately, while both metabolites show strong oral absorption trends, future structural modifications must focus on rigidifying the prolylleucine chain and removing the specific groups driving CYP2E1 and endocrine cross-reactivity.