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1.
J Med Chem ; 66(15): 10473-10496, 2023 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-37427891

RESUMO

TYK2 is a key mediator of IL12, IL23, and type I interferon signaling, and these cytokines have been implicated in the pathogenesis of multiple inflammatory and autoimmune diseases such as psoriasis, rheumatoid arthritis, lupus, and inflammatory bowel diseases. Supported by compelling data from human genome-wide association studies and clinical results, TYK2 inhibition through small molecules is an attractive therapeutic strategy to treat these diseases. Herein, we report the discovery of a series of highly selective pseudokinase (Janus homology 2, JH2) domain inhibitors of TYK2 enzymatic activity. A computationally enabled design strategy, including the use of FEP+, was instrumental in identifying a pyrazolo-pyrimidine core. We highlight the utility of computational physics-based predictions used to optimize this series of molecules to identify the development candidate 30, a potent, exquisitely selective cellular TYK2 inhibitor that is currently in Phase 2 clinical trials for the treatment of psoriasis and psoriatic arthritis.


Assuntos
Artrite Reumatoide , Doenças Autoimunes , Psoríase , Humanos , TYK2 Quinase , Estudo de Associação Genômica Ampla , Doenças Autoimunes/tratamento farmacológico , Psoríase/tratamento farmacológico
2.
J Chem Theory Comput ; 17(4): 2630-2639, 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33779166

RESUMO

We present a reliable and accurate solution to the induced fit docking problem for protein-ligand binding by combining ligand-based pharmacophore docking, rigid receptor docking, and protein structure prediction with explicit solvent molecular dynamics simulations. This novel methodology in detailed retrospective and prospective testing succeeded to determine protein-ligand binding modes with a root-mean-square deviation within 2.5 Å in over 90% of cross-docking cases. We further demonstrate these predicted ligand-receptor structures were sufficiently accurate to prospectively enable predictive structure-based drug discovery for challenging targets, substantially expanding the domain of applicability for such methods.


Assuntos
Simulação de Acoplamento Molecular , Proteínas/química , Ligantes , Ligação Proteica
3.
Nature ; 568(7753): 566-570, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30944472

RESUMO

ATP-citrate lyase (ACLY) is a central metabolic enzyme and catalyses the ATP-dependent conversion of citrate and coenzyme A (CoA) to oxaloacetate and acetyl-CoA1-5. The acetyl-CoA product is crucial for the metabolism of fatty acids6,7, the biosynthesis of cholesterol8, and the acetylation and prenylation of proteins9,10. There has been considerable interest in ACLY as a target for anti-cancer drugs, because many cancer cells depend on its activity for proliferation2,5,11. ACLY is also a target against dyslipidaemia and hepatic steatosis, with a compound currently in phase 3 clinical trials4,5. Many inhibitors of ACLY have been reported, but most of them have weak activity5. Here we report the development of a series of low nanomolar, small-molecule inhibitors of human ACLY. We have also determined the structure of the full-length human ACLY homo-tetramer in complex with one of these inhibitors (NDI-091143) by cryo-electron microscopy, which reveals an unexpected mechanism of inhibition. The compound is located in an allosteric, mostly hydrophobic cavity next to the citrate-binding site, and requires extensive conformational changes in the enzyme that indirectly disrupt citrate binding. The observed binding mode is supported by and explains the structure-activity relationships of these compounds. This allosteric site greatly enhances the 'druggability' of ACLY and represents an attractive target for the development of new ACLY inhibitors.


Assuntos
ATP Citrato (pro-S)-Liase/antagonistas & inibidores , ATP Citrato (pro-S)-Liase/ultraestrutura , Compostos de Benzil/farmacologia , Microscopia Crioeletrônica , Inibidores Enzimáticos/farmacologia , ATP Citrato (pro-S)-Liase/química , ATP Citrato (pro-S)-Liase/metabolismo , Difosfato de Adenosina/metabolismo , Regulação Alostérica/efeitos dos fármacos , Compostos de Benzil/química , Sítios de Ligação/efeitos dos fármacos , Ácido Cítrico/metabolismo , Inibidores Enzimáticos/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Domínios Proteicos , Multimerização Proteica , Relação Estrutura-Atividade
4.
PLoS Negl Trop Dis ; 6(4): e1589, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22509414

RESUMO

BACKGROUND: Cercarial elastase is the major invasive larval protease in Schistosoma mansoni, a parasitic blood fluke, and is essential for host skin invasion. Genome sequence analysis reveals a greatly expanded family of cercarial elastase gene isoforms in Schistosoma mansoni. This expansion appears to be unique to S. mansoni, and it is unknown whether gene duplication has led to divergent protease function. METHODS: Profiling of transcript and protein expression patterns reveals that cercarial elastase isoforms are similarly expressed throughout the S. mansoni life cycle. Computational modeling predicts key differences in the substrate-binding pockets of various cercarial elastase isoforms, suggesting a diversification of substrate preferences compared with the ancestral gene of the family. In addition, active site labeling of SmCE reveals that it is activated prior to exit of the parasite from its intermediate snail host. CONCLUSIONS: The expansion of the cercarial gene family in S. mansoni is likely to be an example of gene dosage. In addition to its critical role in human skin penetration, data presented here suggests a novel role for the protease in egress from the intermediate snail host. This study demonstrates how enzyme activity-based analysis complements genomic and proteomic studies, and is key in elucidating proteolytic function.


Assuntos
Elastase Pancreática/genética , Elastase Pancreática/metabolismo , Schistosoma mansoni/enzimologia , Sequência de Aminoácidos , Animais , Sítios de Ligação , Cercárias/enzimologia , Cercárias/genética , Cricetinae , Perfilação da Expressão Gênica , Mesocricetus , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Dinâmica Molecular , Dados de Sequência Molecular , Elastase Pancreática/química , Ligação Proteica , Proteólise , Schistosoma mansoni/genética , Homologia de Sequência de Aminoácidos , Caramujos
5.
J Med Chem ; 55(7): 3163-9, 2012 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-22394492

RESUMO

We evaluate experimentally and computationally the membrane permeability of matched sets of peptidic small molecules bearing natural or bioisosteric unnatural amino acids. We find that the intentional introduction of hydrogen bond acceptor-donor pairs in such molecules can improve membrane permeability while retaining or improving other favorable drug-like properties. We employ an all-atom force field based method to calculate changes in free energy associated with the transfer of the peptidic molecules from water to membrane. This computational method correctly predicts rank order experimental permeability trends within congeneric series and is much more predictive than calculations (e.g., clogP) that do not consider three-dimensional conformation.


Assuntos
Aminoácidos/química , Permeabilidade da Membrana Celular , Peptídeos/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Aminoácidos/síntese química , Aminoácidos/farmacocinética , Animais , Compostos de Benzil/síntese química , Compostos de Benzil/química , Compostos de Benzil/farmacocinética , Transporte Biológico Ativo , Carbamatos/síntese química , Carbamatos/química , Carbamatos/farmacocinética , Linhagem Celular , Difusão , Cães , Ligação de Hidrogênio , Indóis/síntese química , Indóis/química , Indóis/farmacocinética , Modelos Moleculares , Nitrilas/síntese química , Nitrilas/farmacocinética , Peptídeos/síntese química , Peptídeos/farmacocinética , Conformação Proteica , Piridinas/síntese química , Piridinas/química , Piridinas/farmacocinética , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , Termodinâmica
6.
J Biol Chem ; 281(51): 39285-39293, 2006 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-17012233

RESUMO

Acyl carrier proteins play a central role in metabolism by transporting substrates in a wide variety of pathways including the biosynthesis of fatty acids and polyketides. However, despite their importance, there is a paucity of direct structural information concerning the interaction of ACPs with enzymes in these pathways. Here we report the structure of an acyl-ACP substrate bound to the Escherichia coli fatty acid biosynthesis enoyl reductase enzyme (FabI), based on a combination of x-ray crystallography and molecular dynamics simulation. The structural data are in agreement with kinetic studies on wild-type and mutant FabIs, and reveal that the complex is primarily stabilized by interactions between acidic residues in the ACP helix alpha2 and a patch of basic residues adjacent to the FabI substrate-binding loop. Unexpectedly, the acyl-pantetheine thioester carbonyl is not hydrogen-bonded to Tyr(156), a conserved component of the short chain alcohol dehydrogenase/reductase superfamily active site triad. FabI is a proven target for drug discovery and the present structure provides insight into the molecular determinants that regulate the interaction of ACPs with target proteins.


Assuntos
Proteína de Transporte de Acila/química , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/química , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/fisiologia , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/fisiologia , Escherichia coli/enzimologia , Proteína de Transporte de Acila/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Escherichia coli/metabolismo , Ácido Graxo Sintase Tipo II , Ligação de Hidrogênio , Cinética , Modelos Químicos , Modelos Moleculares , Mutação , Ligação Proteica , Conformação Proteica , Estrutura Secundária de Proteína , Especificidade por Substrato , Tirosina/química
7.
J Med Chem ; 49(15): 4574-80, 2006 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-16854062

RESUMO

Keeping pace with emerging drug resistance in clinically important pathogens will be greatly aided by inexpensive yet reliable computational methods that predict the binding affinities of ligands for drug targets. We present results using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method to calculate the affinity of a series of triclosan analogues for the E. coli enoyl reductase FabI, spanning a 450000-fold range of binding affinities. Significantly, a high correlation is observed between the calculated binding energies and those determined experimentally. Further examination indicates that the van der Waals energies are the most correlated component of the total affinity (r2 = 0.74), indicating that the shape of the inhibitor is very important in defining the binding energies for this system. The validation of MM-PBSA for the E coli FabI system serves as a platform for inhibitor design efforts focused on the homologous enzyme in Staphylococcus aureus and Mycobacterium tuberculosis.


Assuntos
Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/antagonistas & inibidores , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/química , Proteínas de Escherichia coli/antagonistas & inibidores , Proteínas de Escherichia coli/química , Relação Quantitativa Estrutura-Atividade , Triclosan/análogos & derivados , Triclosan/química , Sítios de Ligação , Ácido Graxo Sintase Tipo II , Ligação de Hidrogênio , Modelos Moleculares , NAD/química , Ligação Proteica , Termodinâmica
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