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In silico study on identification of novel MALT1 allosteric inhibitors

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), which plays a crucial role in the nuclear factor-kappa B (NF-κB) activation signaling pathway as a paracaspase, is a new target for immunomodulatory and antitumor drugs. Here, novel inhibitors that target MALT1 allosteric si...

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Detalles Bibliográficos
Autores principales: Zhang, Jinrui, Ren, Li, Wang, Ye, Fang, Xuexun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9076111/
https://www.ncbi.nlm.nih.gov/pubmed/35540679
http://dx.doi.org/10.1039/c9ra07036b
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author Zhang, Jinrui
Ren, Li
Wang, Ye
Fang, Xuexun
author_facet Zhang, Jinrui
Ren, Li
Wang, Ye
Fang, Xuexun
author_sort Zhang, Jinrui
collection PubMed
description Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), which plays a crucial role in the nuclear factor-kappa B (NF-κB) activation signaling pathway as a paracaspase, is a new target for immunomodulatory and antitumor drugs. Here, novel inhibitors that target MALT1 allosteric sites were identified by virtual screening FDA-approved drug databases. Paliperidone, a compound that binds to the allosteric site of MALT1, is investigated. An in vitro study found that the proteolytic activity of MALT1 substrate cleavage was blocked by paliperidone. Meanwhile, the MALT1 proteolytic activity was reversible, as demonstrated by the partial recovery of the MALT1 substrate cleavage following compound wash out. The docking analysis of the interaction of MALT1 and paliperidone suggested that two hydrogen bonds formed in the allosteric pocket of MALT1. MALT1 and paliperidone achieved a good equilibrium, as demonstrated by 100 ns molecular dynamic (MD) simulations conducted with the program Gromacs. However, the catalytically active site of the MALT1 complex with paliperidone remained in an inactive conformation. Thus, paliperidone, a noncompetitive and allosteric inhibitor, was screened through in silico and in vitro methods. This study will be of significance for the development of effective and selective drugs that can treat MALT1-driven cancer or autoimmune diseases.
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spelling pubmed-90761112022-05-09 In silico study on identification of novel MALT1 allosteric inhibitors Zhang, Jinrui Ren, Li Wang, Ye Fang, Xuexun RSC Adv Chemistry Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), which plays a crucial role in the nuclear factor-kappa B (NF-κB) activation signaling pathway as a paracaspase, is a new target for immunomodulatory and antitumor drugs. Here, novel inhibitors that target MALT1 allosteric sites were identified by virtual screening FDA-approved drug databases. Paliperidone, a compound that binds to the allosteric site of MALT1, is investigated. An in vitro study found that the proteolytic activity of MALT1 substrate cleavage was blocked by paliperidone. Meanwhile, the MALT1 proteolytic activity was reversible, as demonstrated by the partial recovery of the MALT1 substrate cleavage following compound wash out. The docking analysis of the interaction of MALT1 and paliperidone suggested that two hydrogen bonds formed in the allosteric pocket of MALT1. MALT1 and paliperidone achieved a good equilibrium, as demonstrated by 100 ns molecular dynamic (MD) simulations conducted with the program Gromacs. However, the catalytically active site of the MALT1 complex with paliperidone remained in an inactive conformation. Thus, paliperidone, a noncompetitive and allosteric inhibitor, was screened through in silico and in vitro methods. This study will be of significance for the development of effective and selective drugs that can treat MALT1-driven cancer or autoimmune diseases. The Royal Society of Chemistry 2019-11-29 /pmc/articles/PMC9076111/ /pubmed/35540679 http://dx.doi.org/10.1039/c9ra07036b Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/
spellingShingle Chemistry
Zhang, Jinrui
Ren, Li
Wang, Ye
Fang, Xuexun
In silico study on identification of novel MALT1 allosteric inhibitors
title In silico study on identification of novel MALT1 allosteric inhibitors
title_full In silico study on identification of novel MALT1 allosteric inhibitors
title_fullStr In silico study on identification of novel MALT1 allosteric inhibitors
title_full_unstemmed In silico study on identification of novel MALT1 allosteric inhibitors
title_short In silico study on identification of novel MALT1 allosteric inhibitors
title_sort in silico study on identification of novel malt1 allosteric inhibitors
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9076111/
https://www.ncbi.nlm.nih.gov/pubmed/35540679
http://dx.doi.org/10.1039/c9ra07036b
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