Investigation of MI-2 analogues as MALT1 inhibitors to treat of diffuse large B-Cell lymphoma through combined molecular dynamics simulation, molecular docking and QSAR techniques and design of new inhibitors

Abstract

Mucosa-associated lymphoid tissue lymphoma translocation protein-1 (MALT1) has emerged as a promising therapeutic target for the treatment of activated B cell–like diffuse large B-cell lymphoma (ABC-DLBCL). To develop more potent MALT1 inhibitors, a series of MI-2 analogues were investigated using combined molecular modeling techniques such as molecular dynamics (MD) simulation, molecular docking and quantitative structure-activity relationship (QSAR). 40 ns MD simulations were successfully performed on the docked complexes of reference compound (MI-2) and compound 33 (one of highly active compounds of the data set) to investigate the binding stability and specifying the active site of the MALT1 enzyme in interaction with inhibitors. A few key residues (GLY416 and GLU500) at the binding site of MALT1 enzyme were identified. Using molecular docking was understood that hydroxyl groups along with groups of dichlorophenyl, chlorobenzyl and fluorobenzyl help to create interactions between the MI-2 analogues and enzyme residues to stabilize the conformation of compounds at the binding pocket. A robust and reliable QSAR model, as evidenced by the high R2, Q2LOO and R2ext values (0.933, 0.891 and 0.970, respectively), was gained based on the MI-2 analogues to predict the quantitative chemical-biological relationship and predict the inhibitory activity of new drug compounds. Then ten new MI-2 analogues have been designed that provide better inhibitory activity with the MALT1 enzyme than the reference compounds.