Journal
JOURNAL OF MOLECULAR STRUCTURE
Volume 1180, Issue -, Pages 708-722Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.molstruc.2018.12.022
Keywords
MALT1; MI-2 analogues; Molecular dynamics (MD) simulation; Molecular docking; QSAR
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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 R-2, Q(LOO)(2) and R-ext(2) 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. (C) 2018 Elsevier B.V. All rights reserved.
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