Integrated Phenotypic and Molecular Interaction Profiling of Cyclic Dipeptides Derived from Leuconostoc citreum LabMP-A03 for Anti-Cancer Drug-Likeness Evaluation

다국어 초록 (Multilingual Abstract)

Cyclic dipeptides (CDPs, 2,5-diketopiperazines) are significantly emerging as promising anti-cancer scaffolds due to their chemical and structural stability, bioavailability, rigidity, and diverse biological activities. In this study, we evaluated the drug-likeness and anti-cancer potential of CDPs isolated from Leuconostoc citreum LabMP-A03 using a novel integrative approach combining phenotypic screening with molecular interaction profiling. Initially, cancer cell-based assays were employed to assess cytotoxicity and selective growth inhibition across a panel of human cancer cell lines, including MCF-7, A549, and HCT-116. Lead CDPs demonstrating potent and selective cytotoxicity were further investigated through 3D docking simulations with key oncogenic targets (e.g., Bcl-2, EGFR, and HDAC1), revealing high binding affinities and favorable interaction conformations. Unlike conventional QSAR or descriptor-based filtering, this approach emphasizes functional validation and direct target engagement. The parallel in vitro ADME assessments showed acceptable membrane permeability and metabolic stability, supporting their therapeutic potential. In addition, transcriptomic profiling of treated cancer cells identified differentially expressed genes associated with apoptosis and cell cycle arrest, confirming mechanistic relevance. This multidimensional evaluation supports the candidacy of L. citreum-derived CDPs as structurally novel and biologically potent lead compounds. These novel findings lay the groundwork for the preclinical development of postbiotic-derived anti-cancer therapeutics through a mechanism-informed selection pipeline.