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1.
iScience ; 27(2): 108968, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38327788

RESUMO

Excessive or aberrant NLRP3 inflammasome activation has been implicated in the progression and initiation of many inflammatory conditions; however, currently no NLRP3 inflammasome inhibitors have been approved for therapeutic use in the clinic. Here we have identified that the natural product brazilin effectively inhibits both priming and activation of the NLRP3 inflammasome in cultured murine macrophages, a human iPSC microglial cell line and in a mouse model of acute peritoneal inflammation. Through computational modeling, we predict that brazilin can adopt a favorable binding pose within a site of the NLRP3 protein which is essential for its conformational activation. Our results not only encourage further evaluation of brazilin as a therapeutic agent for NLRP3-related inflammatory diseases, but also introduce this small-molecule as a promising scaffold structure for the development of derivative NLRP3 inhibitor compounds.

2.
Molecules ; 27(19)2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36234744

RESUMO

The NLRP3 inflammasome is currently an exciting target for drug discovery due to its role in various inflammatory diseases; however, to date, no NLRP3 inhibitors have reached the clinic. Several studies have used natural products as hit compounds to facilitate the design of novel selective NLRP3 inhibitors. Here, we review selected natural products reported in the literature as NLRP3 inhibitors, with a particular focus on those targeting gout. To complement this survey, we also report a virtual screen of the ZINC20 natural product database, predicting favored chemical features that can aid in the design of novel small molecule NLRP3 inhibitors.


Assuntos
Produtos Biológicos , Gota , Produtos Biológicos/farmacologia , Humanos , Inflamassomos , Interleucina-1beta , Proteína 3 que Contém Domínio de Pirina da Família NLR
3.
Protein Sci ; 31(10): e4420, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36173167

RESUMO

The NLRP3 inflammasome is a cytoplasmic complex that regulates the activation of inflammatory cytokines and, given its implication in a range of diseases, is an important therapeutic target. The cofactor ATP and the centrosomal kinase NEK7 are important for NLRP3 activation. Here we have constructed and simulated computational models of full-length monomeric NLRP3 to shed light on the importance of NEK7 and cofactor interactions for its conformation and dynamics in aqueous solution. We find that molecular dynamics simulation reproduces well the features of the recently published cryo-EM structure of the ADP-bound NLRP3-NEK7 complex; on the removal of NEK7, the NLRP3 molecule adopts a more compact closed form during simulations. Replacement of ADP by ATP promotes a rearrangement of hydrogen-bonding interactions, domain interfaces, and a degree of opening of the NLRP3 conformation. We also examine the dynamics of an acidic loop of the LRR domain of NLRP3, which samples in a region observed in the NEK7-bound cryo-EM structure but not in an oligomeric form of inactive NLRP3. During the molecular dynamics simulations of NLRP3, we find some plasticity in its topology that suggests access routes for ATP to the cofactor pocket not immediately evident from the existing NEK7-bound cryo-EM structure. These computed dynamical trajectories of NLRP3 provide insight into coordinates of deformation that may be key for cofactor binding and inflammasome activation.


Assuntos
Inflamassomos , Quinases Relacionadas a NIMA , Proteína 3 que Contém Domínio de Pirina da Família NLR , Difosfato de Adenosina , Trifosfato de Adenosina , Simulação por Computador , Citocinas/metabolismo , Hidrogênio , Inflamassomos/química , Inflamassomos/metabolismo , Quinases Relacionadas a NIMA/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo
4.
J Med Chem ; 65(6): 4783-4797, 2022 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-35290041

RESUMO

A set of meta-substituted 3-arylisoquinolinones have been identified that show substantial cytotoxicity in breast, liver, lung and colon cancer cell lines; these are up to 700-fold more active than the corresponding para analogues. These compounds were initially proposed as inhibitors of N-ribosyl dihydronicotinamide (NRH): quinone oxidoreductase 2 (NQO2) but were found to be inactive against the enzyme. Instead, COMPARE analysis suggested that 6-fluoro-3-(meta-fluorophenyl)isoquinolin-1(2H)-one (4) could mimic colchicine and interact with microtubules, a recognized target for cancer therapy. Subsequent docking, molecular dynamics simulations, and free energy analysis further suggested that compound 4 bound well into the colchicine-binding pocket of tubulin. Indeed, 4 suppressed tubulin polymerization, caused G2/M cell cycle arrest, and induced apoptosis. Also, 4 inhibited the formation of endothelial cell capillary-like tubes and further disrupted the structure of preestablished tubes; the effects were not observed with para analogue 5. In accordance with this, the computed free energy of binding of 5 to tubulin was lower in magnitude than that for 4 and appeared to arise in part from the inability of the para substituent to occupy a tubulin subpocket, which is possible in the meta orientation. In conclusion, the antiproliferative potential of the novel 3-arylisoquinolinones is markedly influenced by a subtle change in the structure (meta versus para). The meta-substituted isoquinolinone 4 is a microtubule-destabilizing agent with potential tumor-selectivity and antiangiogenic and vascular disrupting features.


Assuntos
Antineoplásicos , Tubulina (Proteína) , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células , Colchicina/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Microtúbulos , Estrutura Molecular , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química
5.
Chem Cent J ; 11(1): 102, 2017 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-29086906

RESUMO

BACKGROUND: Rhodanines and quinazolinones have been reported to possess various pharmacological activities. RESULTS: A novel series of twenty quinazolinone-based rhodanines were synthesized via Knoevenagel condensation between 4-[3-(substitutedphenyl)-3,4-dihydro-4-oxoquinazolin-2-yl)methoxy]substituted-benzaldehydes and rhodanine. Elemental and spectral analysis were used to confirm structures of the newly synthesized compounds. The newly synthesized compounds were biologically evaluated for in vitro cytotoxic activity against the human fibrosarcoma cell line HT-1080 as a preliminary screen using the MTT assay. CONCLUSIONS: All the target compounds were active, displaying IC50 values roughly in the range of 10-60 µM. Structure-activity relationship study revealed that bulky, hydrophobic, and electron withdrawing substituents at the para-position of the quinazolinone 3-phenyl ring as well as methoxy substitution on the central benzene ring, enhance cytotoxic activity. The four most cytotoxic compounds namely, 45, 43, 47, and 37 were further tested against two human leukemia cell lines namely, HL-60 and K-562 and showed cytotoxic activity in the low micromolar range with compound 45 being the most active, having IC50 values of 1.2 and 1.5 µM, respectively. Interestingly, all four compounds were devoid of cytotoxicity against normal human fibroblasts strain AG01523, indicating that the synthesized rhodanines may be selectively toxic against cancer cells. Mechanistic studies revealed that the most cytotoxic target compounds exhibit pro-apoptotic activity and trigger oxidative stress in cancer cells.

6.
Bioorg Med Chem Lett ; 27(20): 4760-4764, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28935265

RESUMO

A series of quinazolinone-based rhodanine-3-acetic acids was synthesized and tested for in vitro aldose reductase inhibitory activity. All the target compounds displayed nanomolar activity against the target enzyme. Compounds 3a, 3b, and 3e exhibited almost 3-fold higher activity as compared to the only marketed reference drug epalrestat. Structure-activity relationship studies indicated that bulky substituents at the 3-phenyl ring of the quinazolinone moiety are generally not tolerated in the active site of the enzyme. Insertion of a methoxy group on the central benzylidene ring was found to have a variable effect on ALR-2 activity depending on the nature of peripheral quinazolinone ring substituents. Removal of the acetic acid moiety led to inactive or weakly active target compounds. Docking and molecular dynamic simulations of the most active rhodanine-3-acetic acid derivatives were also carried out, to provide the basis for further structure-guided design of novel inhibitors.


Assuntos
Aldeído Redutase/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Quinazolinonas/química , Rodanina/química , Ácido Acético/química , Aldeído Redutase/metabolismo , Sítios de Ligação , Inibidores Enzimáticos/metabolismo , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Rodanina/análogos & derivados , Rodanina/síntese química , Rodanina/metabolismo , Relação Estrutura-Atividade , Termodinâmica , Tiazolidinas/química , Tiazolidinas/metabolismo
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