In Silico Identification and Characterization of Spiro [1,2,4]triazolo[1,5-<i>c</i>]quinazolines as Diacylglycerol Kinase α Modulators

This study unveils a new class of spiro[1,2,4]triazolo[1,5-c]quinazoline derivatives as promising diacylglycerol kinase α (DGKα) modulators, a target implicated in cancer, neurological disorders, and immune dysfunction. Through structure-based computational design using the CB-Dock2 platform with human DGKα EF-hand domains (PDB ID: 6IIE), 40 novel compounds were systematically evaluated along established inhibitors (ritanserin, R59022, R59949, BMS502, and (5Z,2E)-CU-3) across five distinct binding pockets. Several compounds demonstrated remarkable binding profiles at the level or surpassing reference compounds. The physicochemical analysis revealed balanced drug-like properties with favorable molecular weights (252-412 g/mol) and appropriate three-dimensionality. Toxicological assessment indicated reassuring safety profiles with predicted LD50 values of 1000-2000 mg/kg and minimal hepatotoxicity, carcinogenicity, and mutagenicity potential. Notably, compound 33 (adamantyl-substituted) emerged as exceptionally promising, exhibiting strong binding affinity, moderate solubility, and selective CYP inhibition patterns that minimize drug-drug interaction risks. Detailed molecular interaction mapping identified critical binding determinants, including strategic hydrogen bonding with TRP151, GLU166, and ARG126. The multidimensional evaluation identified compounds 13, 18, 33, and 40 as particularly promising candidates that balance potent target engagement with favorable pharmaceutical profiles, establishing this scaffold as a valuable platform for developing next-generation therapeutics targeting DGKα-mediated signaling pathways.