Discovery of novel 1,3,4-oxadiazole derivatives as anticancer agents targeting thymidine phosphorylase: pharmacophore modelling, virtual screening, molecular docking, ADMET and DFT analysis

Thymidine phosphorylase (TP) is a key enzyme involved in angiogenesis, tumour growth and closely linked to cancer progression and metastasis. This study represents the first comprehensive 3D-QSAR pharmacophore-based approach to identifying potential 1,3,4-oxadiazole derivatives as targeted TPIs for anticancer therapy. A dataset of 76 analogues with an experimental IC₅₀ values was used to develop pharmacophore models. The BEST conformation method identified an optimal model (Hypo 2), featuring HBA, HBD and RA as key activity determinants with strong statistical validation (<i>r</i>² = 0.69, ΔCost = 77.41, <i>Q</i>² = 0.68 and MAE = 0.23). A virtual screening of 12,353 drug-like 1,3,4-oxadiazole compounds from PubChem and ChEMBL yielded 329 potential TPIs (IC₅₀ &lt; 10 μM). MD Docking using CDOCKER (PDB ID: 1UOU) identified the top hits interacting with critical TP residues (Thr151, Gly152, Lys221, Ser217, Thr118). ADMET analysis confirmed their drug-likeness with no significant toxicity. ChEMBL2058305 exhibited the highest binding stability (−85.508 kcal/mol), the lowest HOMO-LUMO gap (0.066 ha), and superior TP affinity, highlighting its potential as a promising TP inhibitor for anticancer therapy. This first report with integration of pharmacophore modelling, virtual screening, MD Docking, ADMET, MMGBSA and DFT will be beneficial for the discovery of novel TPIs.