Application of Cyclic Dipeptides in ADMET Analysis: A Structure-Based Evaluation Approach

다국어 초록 (Multilingual Abstract)

Cyclic dipeptides (CDPs, 2,5-diketopiperazines) are small, conformationally constrained metabolites that often show bioactivity and favorable stability. This study aimed to evaluate CDPs (2,5-DKPs) as ADMET-compatible scaffolds through a structure-based in silico workflow, using cyclo(Met-Pro) isolated from Lactobacillus plantarum LBP-K10 as a representative case. Structural information International Chemical Identifier (InChI) was obtained from NIST/PubChem, and physicochemical descriptors (molecular weight, cLogP, hydrogen-bond donors and acceptors, topological polar surface area, rotatable bonds, sp3 fraction, and QED) were computed/benchmarked against Lipinski and Veber filters. Multi-endpoint predictions were then generated for aqueous solubility (ESOL), intestinal absorption and Caco-2 permeability, blood-brain barrier penetration (Clark logBB), P-gp liability, cytochrome P450 interaction risk, and key toxicity endpoints (Ames mutagenicity, hepatotoxicity, and hERG inhibition). Cyclo(Met-Pro) occupied classical oral drug-like space (MW 228.3 Da, cLogP 1.07, TPSA 52.9 Ų, QED 0.79) and was predicted to be moderately soluble (logS−1.73), highly absorbed, and low risk for major CYP inhibition, genotoxicity, and cardiotoxicity, with borderline BBB exposure (logBB−0.48). This integrated assessment links structural motifs to predicted absorption and safety, offering a transparent template for future systematic experimental validation. Collectively, the results support CDPs as rational starting points for probiotic-derived small-molecule leads and guide the design of CDP libraries for early ADMET screening.