A multi-Level Study of 20S proteasome inhibitors: an integrated approach combining chemistry and Modelling

In view of the important role of 20S proteasome inhibitors in the treatment of multiple myeloma, a 2D-QSAR study was developed using the Monte Carlo approach for 41 peptide boronic acids (PBA) characterised by the CT-L activity of the human 20S proteasome. The QSAR models were generated using six target functions: TF₀, TF_1, TF_2, TF_3, TF₄ and TF₅. Among twenty-four models QSAR developed, the best (model-23 using split-1) was selected based on important statistical performance. Subsequently, the structural fragments responsible for the enhancement of CT-L activity were identified and used to propose new potent inhibitors. Covalent molecular docking was performed for the designed molecules and the reference drug Ixazomib using two human 20S proteasome proteins. All of these inhibitors showed significant binding affinity values, characterised by the formation of a covalent bond between the boron atom of the ligands and the oxygen atom of the threonine residue in position-1. These inhibitors showed good predicted ADMET properties. Two designed inhibitors, P-05 and P-07, were selected to perform MD simulations for 200 ns and to calculate the free binding energy on the two proteins. Finally, the synthesis pathway for P-05 and P-07 was proposed.