Experimentally Validated Novel Factor XIIa Inhibitors Identified by Docking and Quantum Chemical Post‐processing

Abstract Antithrombotic agents based on factor XIIa inhibitors can become a new class of drugs to manage conditions associated with thrombosis. Herein, we report identification of two novel classes of factor XIIa inhibitors. The first one is triazolopyrimidine derivatives designed on the basis of the literature aminotriazole hit and identified using virtual screening of the focused library. The second class is a spirocyclic furo[3,4‐ c ]pyrrole derivatives identified by virtual screening of a large chemical library of drug‐like compounds performed in a previous study but confirmed in vitro here. In both cases, the prediction of inhibitory activity is based on the score of the SOL docking program, which uses the MMFF94 force field to calculate the binding energy. For the best ligands selected in virtual screening of the large chemical library, postprocessing with the PM7 semiempirical quantum‐chemical method was used to calculate the enthalpy of protein‐ligand binding to prioritize 16 compounds for testing in enzymatic assay, and one of them demonstrated micromolar activity. For triazolopyrimidine library, 21 compounds were prioritized for the testing based on docking scores, and visual inspection of docking poses. Of these, 4 compounds showed inhibition of factor XIIa at 30 μM.