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

A new class of spiro[1,2,4]triazolo[1,5-<i>c</i>]quinazoline derivatives is presented as promising modulators of diacylglycerol kinase α (DGK-α), a target implicated in cancer, neurological disorders, and immune dysfunction. Through structure-based computational design using the CB-Dock2 platform with human DGK-α (PDB ID: 6IIE), 40 novel compounds were systematically evaluated along with established inhibitors (ritanserin, R59022, R59949, BMS502, and (5<i>Z</i>,2<i>E</i>)-CU-3) across five distinct binding pockets. Several compounds demonstrated binding profiles at the level of or surpassing the reference compounds. The physicochemical analysis revealed balanced drug-like properties with favorable molecular weights (252-412 g/mol) and appropriate three-dimensionality. The toxicological assessment indicated reassuring safety profiles with predicted LD₅₀ values of 1000-2000 mg/kg and minimal hepatotoxicity, carcinogenicity, and mutagenicity potential. Notably, compound <b>33</b> (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 <b>13</b>, <b>18</b>, <b>33</b>, and <b>40</b> 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 DGK-α -mediated signaling pathways.