A calculation method for designing newTrypanosoma brucei leucyl-tRNA synthetase inhibitors: Combining QSAR and molecular docking technology

Abstract

Leucyl-tRNA synthetase (LeuRS) is a promising target for novel antitrypanosomal agents. We conducted two-dimsional 9two2D-QSAR (HQSAR) and 3D-QSAR (Topomer CoMFA) studies on 37 Trypanosoma brucei LeuRS (TbLeuRS) inhibitors with different structures and potencies to identify the structural features for more LeuRS inhibitors. In the Topomer CoMFA model constructed based on the optimal fragment cutting mode, the cross-validation coefficient q 2 and the non-cross-validation coefficient r 2 are 0.624 and 0.774, respectively, and external validation parameters Q F 1 2 , Q F 2 2 , CCC and r pred 2 are 0.932, 0.931, 0.960 and 0.932, respectively. The best HQSAR model uses atoms, bonds, hydrogen atoms, and chirality as fragment distinctions, 7-8 as the fragment size, and three as the optimal principal component number. This model shows a cross-validated q 2 value of 0.721, a non-cross-validated r 2 value of 0.836, and r pred 2 of 0.923. The steric field maps, electrostatic field maps, and atomic contribution maps of the two models provide the structural characteristics of the inhibitory efficacy. Twelve promising new inhibitors were successfully designed and the models were validated by molecular docking. Finally, we used ADMET analysis to reveal that the designed inhibitors have excellent oral bioavailability and drugability. .