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1.
Biochemistry ; 56(27): 3454-3462, 2017 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-28632393

RESUMO

Human FABP5 and FABP7 are intracellular endocannabinoid transporters. SBFI-26 is an α-truxillic acid 1-naphthyl monoester that competitively inhibits the activities of FABP5 and FABP7 and produces antinociceptive and anti-inflammatory effects in mice. The synthesis of SBFI-26 yields several stereoisomers, and it is not known how the inhibitor binds the transporters. Here we report co-crystal structures of SBFI-26 in complex with human FABP5 and FABP7 at 2.2 and 1.9 Å resolution, respectively. We found that only (S)-SBFI-26 was present in the crystal structures. The inhibitor largely mimics the fatty acid binding pattern, but it also has several unique interactions. Notably, the FABP7 complex corroborates key aspects of the ligand binding pose at the canonical site previously predicted by virtual screening. In FABP5, SBFI-26 was unexpectedly found to bind at the substrate entry portal region in addition to binding at the canonical ligand-binding pocket. Our structural and binding energy analyses indicate that both R and S forms appear to bind the transporter equally well. We suggest that the S enantiomer observed in the crystal structures may be a result of the crystallization process selectively incorporating the (S)-SBFI-26-FABP complexes into the growing lattice, or that the S enantiomer may bind to the portal site more rapidly than to the canonical site, leading to an increased local concentration of the S enantiomer for binding to the canonical site. Our work reveals two binding poses of SBFI-26 in its target transporters. This knowledge will guide the development of more potent FABP inhibitors based upon the SBFI-26 scaffold.


Assuntos
Analgésicos/metabolismo , Ciclobutanos/metabolismo , Ácidos Dicarboxílicos/metabolismo , Proteína 7 de Ligação a Ácidos Graxos/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Modelos Moleculares , Proteínas Supressoras de Tumor/metabolismo , Analgésicos/química , Analgésicos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/metabolismo , Anti-Inflamatórios não Esteroides/farmacologia , Apoproteínas/antagonistas & inibidores , Apoproteínas/química , Apoproteínas/genética , Apoproteínas/metabolismo , Sítios de Ligação , Domínio Catalítico , Biologia Computacional , Cristalografia por Raios X , Ciclobutanos/química , Ciclobutanos/farmacologia , Ácidos Dicarboxílicos/química , Ácidos Dicarboxílicos/farmacologia , Proteína 7 de Ligação a Ácidos Graxos/antagonistas & inibidores , Proteína 7 de Ligação a Ácidos Graxos/química , Proteína 7 de Ligação a Ácidos Graxos/genética , Proteínas de Ligação a Ácido Graxo/antagonistas & inibidores , Proteínas de Ligação a Ácido Graxo/química , Proteínas de Ligação a Ácido Graxo/genética , Humanos , Ligantes , Camundongos , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Conformação Proteica , Proteínas Recombinantes , Estereoisomerismo , Proteínas Supressoras de Tumor/antagonistas & inibidores , Proteínas Supressoras de Tumor/química , Proteínas Supressoras de Tumor/genética
2.
Mol Pain ; 13: 1744806917697007, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28326944

RESUMO

Background Fatty-acid-binding proteins (FABPs) are intracellular carriers for endocannabinoids, N-acylethanolamines, and related lipids. Previous work indicates that systemically administered FABP5 inhibitors produce analgesia in models of inflammatory pain. It is currently not known whether FABP inhibitors exert their effects through peripheral or central mechanisms. Here, we examined FABP5 distribution in dorsal root ganglia and spinal cord and examined the analgesic effects of peripherally and centrally administered FABP5 inhibitors. Results Immunofluorescence revealed robust expression of FABP5 in lumbar dorsal root ganglia. FABP5 was distributed in peptidergic calcitonin gene-related peptide-expressing dorsal root ganglia and non-peptidergic isolectin B4-expressing dorsal root ganglia. In addition, the majority of dorsal root ganglia expressing FABP5 also expressed transient receptor potential vanilloid 1 (TRPV1) and peripherin, a marker of nociceptive fibers. Intraplantar administration of FABP5 inhibitors reduced thermal and mechanical hyperalgesia in the complete Freund's adjuvant model of chronic inflammatory pain. In contrast to its robust expression in dorsal root ganglia, FABP5 was sparsely distributed in the lumbar spinal cord and intrathecal administration of FABP inhibitor did not confer analgesic effects. Administration of FABP inhibitor via the intracerebroventricular (i.c.v.) route reduced thermal hyperalgesia. Antagonists of peroxisome proliferator-activated receptor alpha blocked the analgesic effects of peripherally and i.c.v. administered FABP inhibitor while antagonism of cannabinoid receptor 1 blocked the effects of peripheral FABP inhibition and a TRPV1 antagonist blocked the effects of i.c.v. administered inhibitor. Although FABP5 and TRPV1 were co-expressed in the periaqueductal gray region of the brain, which is known to modulate pain, knockdown of FABP5 in the periaqueductal gray using adeno-associated viruses and pharmacological FABP5 inhibition did not produce analgesic effects. Conclusions This study demonstrates that FABP5 is highly expressed in nociceptive dorsal root ganglia neurons and FABP inhibitors exert peripheral and supraspinal analgesic effects. This indicates that peripherally restricted FABP inhibitors may serve as a new class of analgesic and anti-inflammatory agents.


Assuntos
Analgésicos/uso terapêutico , Sistema Nervoso Central/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Hiperalgesia/tratamento farmacológico , Proteínas de Neoplasias/metabolismo , Dor/tratamento farmacológico , Nervos Periféricos/metabolismo , Analgésicos/farmacologia , Animais , Ácidos Araquidônicos/metabolismo , Sistema Nervoso Central/efeitos dos fármacos , Ciclobutanos/uso terapêutico , Ácidos Dicarboxílicos/uso terapêutico , Modelos Animais de Doenças , Proteínas de Ligação a Ácido Graxo/genética , Adjuvante de Freund/toxicidade , Gânglios Espinais/metabolismo , Hiperalgesia/etiologia , Inflamação/induzido quimicamente , Inflamação/complicações , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Neoplasias/genética , Dor/complicações , Dor/etiologia , Limiar da Dor/efeitos dos fármacos , Nervos Periféricos/efeitos dos fármacos , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução Genética
3.
Bioorg Med Chem ; 24(24): 6354-6369, 2016 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-27189886

RESUMO

With the emergence of multidrug-resistant bacterial strains, there is a dire need for new drug targets for antibacterial drug discovery and development. Filamentous temperature sensitive protein Z (FtsZ), is a GTP-dependent prokaryotic cell division protein, sharing less than 10% sequence identity with the eukaryotic cell division protein, tubulin. FtsZ forms a dynamic Z-ring in the middle of the cell, leading to septation and subsequent cell division. Inhibition of the Z-ring blocks cell division, thus making FtsZ a highly attractive target. Various groups have been working on natural products and synthetic small molecules as inhibitors of FtsZ. This review summarizes the recent advances in the development of FtsZ inhibitors, focusing on those in the last 5years, but also includes significant findings in previous years.


Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Proteínas de Bactérias/antagonistas & inibidores , Proteínas do Citoesqueleto/antagonistas & inibidores , Descoberta de Drogas , Antibacterianos/síntese química , Antibacterianos/química , Bactérias/química , Bactérias/citologia , Humanos , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade
4.
RSC Med Chem ; 12(1): 78-94, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34046600

RESUMO

Filamenting temperature sensitive protein Z (FtsZ) is an essential bacterial cell division protein and a promising target for the development of new antibacterial therapeutics. As a part of our ongoing SAR studies on 2,5,6-trisubstituted benzimidazoles as antitubercular agents targeting Mtb-FtsZ, a new library of compounds with modifications at the 2 position was designed, synthesized and evaluated for their activity against Mtb-H37Rv. This new library of trisubstituted benzimidazoles exhibited MIC values in the range of 0.004-50 µg mL-1. Compounds 6b, 6c, 20f and 20g showed excellent growth inhibitory activities ranging from 0.004-0.08 µg mL-1. This SAR study has led to the discovery of a remarkably potent compound 20g (MIC 0.0039 µg mL-1; normalized MIC 0.015 µg mL-1). Our 3DQSAR model predicted 20g as the most potent compound in the library.

5.
J Pain Res ; 11: 473-482, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29551907

RESUMO

BACKGROUND: Metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG) yields arachidonic acid (AA), the precursor to proalgesic eicosanoids including prostaglandin E2 (PGE2). Diacylglycerol lipase ß (DAGLß) is an enzyme that synthesizes 2-AG and its inhibition reduces eicosanoid levels and produces antinociceptive effects in models of inflammatory pain. Here we test whether inhibition of DAGLß produces antinociceptive effects in a model of postoperative pain. METHODS: Rats were administered the selective DAGLß inhibitor KT109 or vehicle and underwent plantar incision. Postsurgical pain/disability was examined using evoked (mechanical hyperalgesia), functional (incapacitance/weight bearing), and functional/spontaneous (locomotion) modalities. RESULTS: Activity-based protein profiling confirmed that KT109 inhibited DAGLß in the lumbar spinal cord (LSC) and brain, confirming that it is a systemically active DAGLß inhibitor. Treatment with KT109 reduced basal 2-AG, AA, and PGE2 levels in the liver but not the brain, indicating that DAGLß activity does not significantly contribute to basal PGE2 production within the central nervous system. Plantar incision elevated the levels of 2-AG and PGE2 in the LSC. Although KT109 did not alter postsurgical 2-AG levels in the LSC, it slightly reduced PGE2 levels. In contrast, the clinically efficacious cyclooxygenase inhibitor ketoprofen completely suppressed PGE2 levels in the LSC. Similarly, KT109 had no significant effect upon postsurgical 2-AG, AA, or PGE2 levels at the incision site, while ketoprofen abolished PGE2 production at this location. KT109 and ketoprofen reversed the weight bearing imbalance induced by plantar incision, yet neither KT109 nor ketoprofen had any significant effect on mechanical hyperalgesia. Treatment with ketoprofen partially but significantly rescued the locomotor deficit induced by incision while KT109 was without effect. CONCLUSION: DAGLß is not the principal enzyme that controls 2-AG derived AA and PGE2 production after surgery, and inhibitors targeting this enzyme are unlikely to be efficacious analgesics superior to those already approved to treat acute postoperative pain.

6.
Eur J Med Chem ; 154: 233-252, 2018 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-29803996

RESUMO

Fatty acid binding proteins (FABPs) serve as critical modulators of endocannabinoid signaling by facilitating the intracellular transport of anandamide and whose inhibition potentiates anandamide signaling. Our previous work has identified a novel small-molecule FABP inhibitor, α-truxillic acid 1-naphthyl monoester (SB-FI-26, 3) that has shown efficacy as an antinociceptive and anti-inflammatory agent in rodent models. In the present work, we have performed an extensive SAR study on a series of 3-analogs as novel FABP inhibitors based on computer-aided inhibitor drug design and docking analysis, chemical synthesis and biological evaluations. The prediction of binding affinity of these analogs to target FABP3, 5 and 7 isoforms was performed using the AutoDock 4.2 program, using the recently determined co-crystal structures of 3 with FABP5 and FABP7. The compounds with high docking scores were synthesized and evaluated for their activities using a fluorescence displacement assay against FABP3, 5 and 7. During lead optimization, compound 3l emerged as a promising compound with the Ki value of 0.21 µM for FABP 5, 4-fold more potent than 3 (Ki, 0.81 µM). Nine compounds exhibit similar or better binding affinity than 3, including compounds 4b (Ki, 0.55 µM) and 4e (Ki, 0.68 µM). Twelve compounds are selective for FABP5 and 7 with >10 µM Ki values for FABP3, indicating a safe profile to avoid potential cardiotoxicity concerns. Compounds 4f, 4j and 4k showed excellent selectivity for FABP5 and would serve as other new lead compounds. Compound 3a possessed high affinity and high selectivity for FABP7. Compounds with moderate to high affinity for FABP5 displayed antinociceptive effects in mice while compounds with low FABP5 affinity lacked in vivo efficacy. In vivo pain model studies in mice revealed that exceeding hydrophobicity significantly affects the efficacy. Thus, among the compounds with high affinity to FABP5 in vitro, the compounds with moderate hydrophobicity were identified as promising new lead compounds for the next round of optimization, including compounds 4b and 4j. For select cases, computational analysis of the observed SAR, especially the selectivity of new inhibitors to particular FABP isoforms, by comparing docking poses, interaction map, and docking energy scores has provided useful insights.


Assuntos
Analgésicos/farmacologia , Ciclobutanos/farmacologia , Ésteres/farmacologia , Proteínas de Ligação a Ácido Graxo/antagonistas & inibidores , Analgésicos/síntese química , Analgésicos/química , Animais , Desenho Assistido por Computador , Ciclobutanos/síntese química , Ciclobutanos/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ésteres/síntese química , Ésteres/química , Proteínas de Ligação a Ácido Graxo/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
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