Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 31
Filtrar
Mais filtros








Base de dados
Intervalo de ano de publicação
1.
J Chem Theory Comput ; 20(2): 799-818, 2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38157475

RESUMO

Biomolecular simulations have become an essential tool in contemporary drug discovery, and molecular mechanics force fields (FFs) constitute its cornerstone. Developing a high quality and broad coverage general FF is a significant undertaking that requires substantial expert knowledge and computing resources, which is beyond the scope of general practitioners. Existing FFs originate from only a limited number of groups and organizations, and they either suffer from limited numbers of training sets, lower than desired quality because of oversimplified representations, or are costly for the molecular modeling community to access. To address these issues, in this work, we developed an AMBER-consistent small molecule FF with extensive chemical space coverage, and we provide Open Access parameters for the entire modeling community. To validate our FF, we carried out benchmarks of quantum mechanics (QM)/molecular mechanics conformer comparison and free energy perturbation calculations on several benchmark data sets. Our FF achieves a higher level of performance at reproducing QM energies and geometries than two popular open-source FFs, OpenFF2 and GAFF2. In relative binding free energy calculations for 31 protein-ligand data sets, comprising 1079 pairs of ligands, the new FF achieves an overall root-mean-square error of 1.19 kcal/mol for ΔΔG and 0.92 kcal/mol for ΔG on a subset of 463 ligands without bespoke fitting to the data sets. The results are on par with those of the leading commercial series of OPLS FFs.


Assuntos
Benchmarking , Simulação de Dinâmica Molecular , Termodinâmica , Entropia , Proteínas/química , Ligantes
2.
Bioorg Med Chem Lett ; 94: 129454, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37591316

RESUMO

Activation of the glucagon-like peptide-1 (GLP-1) receptor stimulates insulin release, lowers plasma glucose levels, delays gastric emptying, increases satiety, suppresses food intake, and affords weight loss in humans. These beneficial attributes have made peptide-based agonists valuable tools for the treatment of type 2 diabetes mellitus and obesity. However, efficient, and consistent delivery of peptide agents generally requires subcutaneous injection, which can reduce patient utilization. Traditional orally absorbed small molecules for this target may offer improved patient compliance as well as the opportunity for co-formulation with other oral therapeutics. Herein, we describe an SAR investigation leading to small-molecule GLP-1 receptor agonists that represent a series that parallels the recently reported clinical candidate danuglipron. In the event, identification of a benzyloxypyrimidine lead, using a sensitized high-throughput GLP-1 agonist assay, was followed by optimization of the SAR using substituent modifications analogous to those discovered in the danuglipron series. A new series of 6-azaspiro[2.5]octane molecules was optimized into potent GLP-1 agonists. Information gleaned from cryogenic electron microscope structures was used to rationalize the SAR of the optimized compounds.


Assuntos
Diabetes Mellitus Tipo 2 , Receptor do Peptídeo Semelhante ao Glucagon 1 , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Ensaios de Triagem em Larga Escala , Hipoglicemiantes/farmacologia , Octanos/química , Octanos/farmacologia , Compostos de Espiro/química , Compostos de Espiro/farmacologia
3.
J Chem Theory Comput ; 19(15): 5058-5076, 2023 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-37487138

RESUMO

Binding free energy calculations predict the potency of compounds to protein binding sites in a physically rigorous manner and see broad application in prioritizing the synthesis of novel drug candidates. Relative binding free energy (RBFE) calculations have emerged as an industry-standard approach to achieve highly accurate rank-order predictions of the potency of related compounds; however, this approach requires that the ligands share a common scaffold and a common binding mode, restricting the methods' domain of applicability. This is a critical limitation since complex modifications to the ligands, especially core hopping, are very common in drug design. Absolute binding free energy (ABFE) calculations are an alternate method that can be used for ligands that are not congeneric. However, ABFE suffers from a known problem of long convergence times due to the need to sample additional degrees of freedom within each system, such as sampling rearrangements necessary to open and close the binding site. Here, we report on an alternative method for RBFE, called Separated Topologies (SepTop), which overcomes the issues in both of the aforementioned methods by enabling large scaffold changes between ligands with a convergence time comparable to traditional RBFE. Instead of only mutating atoms that vary between two ligands, this approach performs two absolute free energy calculations at the same time in opposite directions, one for each ligand. Defining the two ligands independently allows the comparison of the binding of diverse ligands without the artificial constraints of identical poses or a suitable atom-atom mapping. This approach also avoids the need to sample the unbound state of the protein, making it more efficient than absolute binding free energy calculations. Here, we introduce an implementation of SepTop. We developed a general and efficient protocol for running SepTop, and we demonstrated the method on four diverse, pharmaceutically relevant systems. We report the performance of the method, as well as our practical insights into the strengths, weaknesses, and challenges of applying this method in an industrial drug design setting. We find that the accuracy of the approach is sufficiently high to rank order ligands with an accuracy comparable to traditional RBFE calculations while maintaining the additional flexibility of SepTop.

4.
J Med Chem ; 65(12): 8208-8226, 2022 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-35647711

RESUMO

Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited because they require injection. Herein, we describe the discovery of the orally bioavailable, small-molecule, GLP-1R agonist PF-06882961 (danuglipron). A sensitized high-throughput screen was used to identify 5-fluoropyrimidine-based GLP-1R agonists that were optimized to promote endogenous GLP-1R signaling with nanomolar potency. Incorporation of a carboxylic acid moiety provided considerable GLP-1R potency gains with improved off-target pharmacology and reduced metabolic clearance, ultimately resulting in the identification of danuglipron. Danuglipron increased insulin levels in primates but not rodents, which was explained by receptor mutagensis studies and a cryogenic electron microscope structure that revealed a binding pocket requiring a primate-specific tryptophan 33 residue. Oral administration of danuglipron to healthy humans produced dose-proportional increases in systemic exposure (NCT03309241). This opens an opportunity for oral small-molecule therapies that target the well-validated GLP-1R for metabolic health.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1 , Hipoglicemiantes , Animais , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos , Hipoglicemiantes/farmacologia , Peptídeos/química
5.
J Chem Inf Model ; 62(4): 785-800, 2022 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-35119861

RESUMO

Fast and accurate assessment of small-molecule dihedral energetics is crucial for molecular design and optimization in medicinal chemistry. Yet, accurate prediction of torsion energy profiles remains challenging as the current molecular mechanics (MM) methods are limited by insufficient coverage of drug-like chemical space and accurate quantum mechanical (QM) methods are too expensive. To address this limitation, we introduce TorsionNet, a deep neural network (DNN) model specifically developed to predict small-molecule torsion energy profiles with QM-level accuracy. We applied active learning to identify nearly 50k fragments (with elements H, C, N, O, F, S, and Cl) that maximized the coverage of our corporate compound library and leveraged massively parallel cloud computing resources for density functional theory (DFT) torsion scans of these fragments, generating a training data set of 1.2 million DFT energies. After training TorsionNet on this data set, we obtain a model that can rapidly predict the torsion energy profile of typical drug-like fragments with DFT-level accuracy. Importantly, our method also provides an uncertainty estimate for the predicted profiles without any additional calculations. In this report, we show that TorsionNet can accurately identify the preferred dihedral geometries observed in crystal structures. Our TorsionNet-based analysis of a diverse set of protein-ligand complexes with measured binding affinity shows a strong association between high ligand strain and low potency. We also present practical applications of TorsionNet that demonstrate how consideration of DNN-based strain energy leads to substantial improvement in existing lead discovery and design workflows. TorsionNet500, a benchmark data set comprising 500 chemically diverse fragments with DFT torsion profiles (12k MM- and DFT-optimized geometries and energies), has been created and is made publicly available.


Assuntos
Redes Neurais de Computação , Teoria Quântica , Ligantes , Simulação de Dinâmica Molecular , Termodinâmica
6.
Phys Chem Chem Phys ; 22(16): 8373-8390, 2020 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-32266895

RESUMO

Recently, molecular fingerprints extracted from three-dimensional (3D) structures using advanced mathematics, such as algebraic topology, differential geometry, and graph theory have been paired with efficient machine learning, especially deep learning algorithms to outperform other methods in drug discovery applications and competitions. This raises the question of whether classical 2D fingerprints are still valuable in computer-aided drug discovery. This work considers 23 datasets associated with four typical problems, namely protein-ligand binding, toxicity, solubility and partition coefficient to assess the performance of eight 2D fingerprints. Advanced machine learning algorithms including random forest, gradient boosted decision tree, single-task deep neural network and multitask deep neural network are employed to construct efficient 2D-fingerprint based models. Additionally, appropriate consensus models are built to further enhance the performance of 2D-fingerprint-based methods. It is demonstrated that 2D-fingerprint-based models perform as well as the state-of-the-art 3D structure-based models for the predictions of toxicity, solubility, partition coefficient and protein-ligand binding affinity based on only ligand information. However, 3D structure-based models outperform 2D fingerprint-based methods in complex-based protein-ligand binding affinity predictions.


Assuntos
Técnicas de Química Analítica/normas , Descoberta de Drogas/métodos , Mapeamento de Peptídeos , Algoritmos , Conjuntos de Dados como Assunto
7.
J Chem Inf Model ; 59(10): 4195-4208, 2019 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-31573196

RESUMO

The energetics of rotation around single bonds (torsions) is a key determinant of the three-dimensional shape that druglike molecules adopt in solution, the solid state, and in different biological environments, which in turn defines their unique physical and pharmacological properties. Therefore, accurate characterization of torsion angle preference and energetics is essential for the success of computational drug discovery and design. Here, we analyze torsional strain in crystal structures of druglike molecules in Cambridge structure database (CSD) and bioactive ligand conformations in protein data bank (PDB), expressing the total strain energy as a sum of strain energy from constituent rotatable bonds. We utilized cloud computing to generate torsion scan profiles of a very large collection of chemically diverse neutral fragments at DFT(B3LYP)/6-31G*//6-31G** or DFT(B3LYP)/6-31+G*//6-31+G** (for sulfur-containing molecule). With the data generated from these ab initio calculations, we performed rigorous analysis of strain due to deviation of observed torsion angles relative to their ideal gas-phase geometries. Contrary to the previous studies based on molecular mechanics, we find that in the crystalline state, molecules generally adopt low-strain conformations, with median per-torsion strain energy in CSD and PDB under one-tenth and one-third of a kcal/mol, respectively. However, for a small fraction (<5%) of motifs, external effects such as steric hindrance and hydrogen bonds result in strain penalty exceeding 2.5 kcal/mol. We find that due to poor quality of PDB structures in general, bioactive structures tend to have higher torsional strain compared to small-molecule crystal conformations. However, in the absence of structural fitting artifacts in PDB structures, protein-induced strain in bioactive conformations is quantitatively similar to those due to the packing forces in small-molecule crystal structures. This analysis allows us to establish strain energy thresholds to help identify biologically relevant conformers in a given ensemble. The work presented here is the most comprehensive study to date that demonstrates the utility and feasibility of gas-phase quantum mechanics (QM) calculations to study conformational preference and energetics of drug-size molecules. Potential applications of this study in computational lead discovery and structure-based design are discussed.


Assuntos
Descoberta de Drogas , Proteínas/química , Bases de Dados de Compostos Químicos , Ligação de Hidrogênio , Ligantes , Conformação Molecular , Estrutura Molecular , Rotação , Bibliotecas de Moléculas Pequenas
8.
Methods Mol Biol ; 2001: 1-15, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31134564

RESUMO

One of the most exciting facets of cyclic peptides is that they have the potential to be orally bioavailable, despite having physical properties well beyond the traditional "Rule-of-5" chemistry space (Lipinski et al., Adv Drug Deliv Rev. 23(1): 3-25, 1997). An important component of meeting this challenge is to design cyclic peptides with good intestinal permeability. Here we discuss the design principles for intestinal permeability that have been developed in recent year. These principles can be subdivided into three regimes: physical property guidelines, design strategies for the macrocyclic ring, and design strategies for side chains. The most important overall aims are to minimize solvent-exposed polarity while keeping size, flexibility, and lipophilicity within favorable ranges, thereby allowing peptide chemists to achieve intestinal permeability in addition to other important properties for their compounds, such as solubility and binding affinity. Here we describe a variety of design strategies that have been developed to help peptide chemists in this endeavor.


Assuntos
Peptídeos Cíclicos/química , Peptídeos Cíclicos/metabolismo , Administração Oral , Alquilação , Células CACO-2 , Ensaios de Triagem em Larga Escala , Humanos , Ligação de Hidrogênio , Intestinos/fisiologia , Membranas Artificiais , Peptídeos Cíclicos/administração & dosagem , Peptoides/síntese química , Peptoides/química , Permeabilidade , Solubilidade
9.
J Med Chem ; 60(23): 9653-9663, 2017 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-29045152

RESUMO

The chemokine receptor CXCR7 is an attractive target for a variety of diseases. While several small-molecule modulators of CXCR7 have been reported, peptidic macrocycles may provide advantages in terms of potency, selectivity, and reduced off-target activity. We produced a series of peptidic macrocycles that incorporate an N-linked peptoid functionality where the peptoid group enabled us to explore side-chain diversity well beyond that of natural amino acids. At the same time, theoretical calculations and experimental assays were used to track and reduce the polarity while closely monitoring the physicochemical properties. This strategy led to the discovery of macrocyclic peptide-peptoid hybrids with high CXCR7 binding affinities (Ki < 100 nM) and measurable passive permeability (Papp > 5 × 10-6 cm/s). Moreover, bioactive peptide 25 (Ki = 9 nM) achieved oral bioavailability of 18% in rats, which was commensurate with the observed plasma clearance values upon intravenous administration.


Assuntos
Peptídeos/química , Peptídeos/farmacologia , Peptoides/química , Peptoides/farmacologia , Receptores CXCR/agonistas , Receptores CXCR/metabolismo , Administração Oral , Animais , Disponibilidade Biológica , Cães , Humanos , Compostos Macrocíclicos/administração & dosagem , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacocinética , Compostos Macrocíclicos/farmacologia , Células Madin Darby de Rim Canino , Masculino , Simulação de Acoplamento Molecular , Peptídeos/administração & dosagem , Peptídeos/farmacocinética , Peptoides/administração & dosagem , Peptoides/farmacocinética , Ratos , Ratos Wistar
10.
Org Biomol Chem ; 15(12): 2501-2506, 2017 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-28266673

RESUMO

The synthesis and in vivo pharmacokinetic profile of an analogue of cyclosporine is disclosed. An acyclic congener was also profiled in in vitro assays to compare cell permeability. The compounds possess similar calculated and measured molecular descriptors however have different behaviors in an RRCK assay to assess cell permeability.


Assuntos
Ciclosporina/farmacocinética , Oligopeptídeos/farmacocinética , Animais , Ciclosporina/administração & dosagem , Ciclosporina/química , Masculino , Conformação Molecular , Oligopeptídeos/administração & dosagem , Oligopeptídeos/química , Ratos , Ratos Wistar , Estereoisomerismo
11.
J Med Chem ; 60(5): 1665-1672, 2017 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-28059508

RESUMO

Macrocyclic peptides are considered large enough to inhibit "undruggable" targets, but the design of passively cell-permeable molecules in this space remains a challenge due to the poorly understood role of molecular size on passive membrane permeability. Using split-pool combinatorial synthesis, we constructed a library of cyclic, per-N-methlyated peptides spanning a wide range of calculated lipohilicities (0 < AlogP < 8) and molecular weights (∼800 Da < MW < ∼1200 Da). Analysis by the parallel artificial membrane permeability assay revealed a steep drop-off in apparent passive permeability with increasing size in stark disagreement with current permeation models. This observation, corroborated by a set of natural products, helps define criteria for achieving permeability in larger molecular size regimes and suggests an operational cutoff, beyond which passive permeability is constrained by a sharply increasing penalty on membrane permeation.


Assuntos
Permeabilidade da Membrana Celular/efeitos dos fármacos , Adsorção , Humanos
12.
ACS Med Chem Lett ; 6(11): 1128-33, 2015 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-26617966

RESUMO

Recent studies in adipose tissue, pancreas, muscle, and macrophages suggest that MAP4K4, a serine/threonine protein kinase may be a viable target for antidiabetic drugs. As part of the evaluation of MAP4K4 as a novel antidiabetic target, a tool compound, 16 (PF-6260933) and a lead 17 possessing excellent kinome selectivity and suitable properties were delivered to establish proof of concept in vivo. The medicinal chemistry effort that led to the discovery of these lead compounds is described herein together with in vivo pharmacokinetic properties and activity in a model of insulin resistance.

13.
Bioorg Med Chem Lett ; 25(22): 5352-6, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26411795

RESUMO

A novel series of spirocyclic-diamine based, isoform non-selective inhibitors of acetyl-CoA carboxylase (ACC) is described. These spirodiamine derivatives were discovered by design of a library to mimic the structural rigidity and hydrogen-bonding pattern observed in the co-crystal structure of spirochromanone inhibitor I. The lead compound 3.5.1 inhibited de novo lipogenesis in rat hepatocytes, with an IC50 of 0.30 µM.


Assuntos
Acetilcoenzima A/metabolismo , Acetil-CoA Carboxilase/antagonistas & inibidores , Descoberta de Drogas , Hepatócitos/efeitos dos fármacos , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Animais , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Hepatócitos/enzimologia , Humanos , Concentração Inibidora 50 , Modelos Biológicos , Estrutura Molecular , Ratos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia
14.
Org Lett ; 17(12): 2928-31, 2015 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-26046483

RESUMO

The effect of peptide-to-peptoid substitutions on the passive membrane permeability of an N-methylated cyclic hexapeptide is examined. In general, substitutions maintained permeability but increased conformational heterogeneity. Diversification with nonproteinogenic side chains increased permeability up to 3-fold. Additionally, the conformational impact of peptoid substitutions within a ß-turn are explored. Based on these results, the strategic incorporation of peptoid residues into cyclic peptides can maintain or improve cell permeability, while increasing access to diverse side-chain functionality.


Assuntos
Células Epiteliais/efeitos dos fármacos , Peptídeos/farmacologia , Permeabilidade/efeitos dos fármacos , Animais , Linhagem Celular , Cães , Células Epiteliais/metabolismo , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Simulação de Dinâmica Molecular , Peptídeos/química , Relação Estrutura-Atividade
15.
J Med Chem ; 58(11): 4581-9, 2015 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-25950816

RESUMO

Cyclic peptide natural products contain a variety of conserved, nonproteinogenic structural elements such as d-amino acids and amide N-methylation. In addition, many cyclic peptides incorporate γ-amino acids and other elements derived from polyketide synthases. We hypothesized that the position and orientation of these extended backbone elements impact the ADME properties of these hybrid molecules, especially their ability to cross cell membranes and avoid metabolic degradation. Here we report the synthesis of cyclic hexapeptide diastereomers containing γ-amino acids (e.g., statines) and systematically investigate their structure-permeability relationships. These compounds were much more water-soluble and, in many cases, were both more membrane permeable and more stable to liver microsomes than a similar non-statine-containing derivative. Permeability correlated well with the extent of intramolecular hydrogen bonding observed in the solution structures determined in the low-dielectric solvent CDCl3, and one compound showed an oral bioavailability of 21% in rat. Thus, the incorporation of γ-amino acids offers a route to increase backbone diversity and improve ADME properties in cyclic peptide scaffolds.


Assuntos
Produtos Biológicos/farmacologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Compostos Macrocíclicos/farmacologia , Microssomos Hepáticos/efeitos dos fármacos , Peptídeos Cíclicos/farmacologia , Solventes/química , Administração Oral , Animais , Disponibilidade Biológica , Produtos Biológicos/química , Fenômenos Químicos , Ligação de Hidrogênio , Compostos Macrocíclicos/administração & dosagem , Compostos Macrocíclicos/química , Espectroscopia de Ressonância Magnética , Masculino , Modelos Moleculares , Estrutura Molecular , Peptídeos Cíclicos/administração & dosagem , Peptídeos Cíclicos/química , Ratos , Ratos Wistar , Relação Estrutura-Atividade
16.
J Med Chem ; 58(9): 4080-5, 2015 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-25839426

RESUMO

Cyclic constraints are incorporated into an 11-residue analogue of the N-terminus of glucagon-like peptide-1 (GLP-1) to investigate effects of structure on agonist activity. Cyclization through linking side chains of residues 2 and 5 or 5 and 9 produced agonists at nM concentrations in a cAMP assay. 2D NMR and CD spectra revealed an N-terminal ß-turn and a C-terminal helix that differentially influenced affinity and agonist potency. These structures can inform development of small molecule agonists of the GLP-1 receptor to treat type 2 diabetes.


Assuntos
Peptídeos Cíclicos/química , Receptores de Glucagon/agonistas , Animais , Células CHO , Dicroísmo Circular , Cricetulus , AMP Cíclico/biossíntese , Receptor do Peptídeo Semelhante ao Glucagon 1 , Humanos , Interações Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Ressonância Magnética Nuclear Biomolecular , Peptídeos Cíclicos/farmacologia , Estrutura Secundária de Proteína , Ensaio Radioligante , Relação Estrutura-Atividade
17.
Org Lett ; 16(23): 6088-91, 2014 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-25412436

RESUMO

Despite the prevalence of head-to-side chain threonine linkages in natural products, their incorporation has been underexplored in synthetic cyclic peptides. Herein we investigate a cyclic peptide scaffold able to undergo an N-O acyl rearrangement. Upon acylation of the amine with diverse carboxylic acids, the resulting cyclic depsipeptides displayed favorable cellular permeability and a conformation similar to the parent peptide. The rearrangement was found to be scaffold and conformation dependent as evidenced by molecular dynamics experiments.


Assuntos
Produtos Biológicos/síntese química , Depsipeptídeos/síntese química , Acilação , Sequência de Aminoácidos , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Depsipeptídeos/química , Depsipeptídeos/farmacologia , Conformação Molecular , Estrutura Molecular , Peptídeos/química , Peptídeos Cíclicos
18.
J Med Chem ; 57(24): 10512-26, 2014 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-25423286

RESUMO

Acetyl-CoA carboxylase (ACC) inhibitors offer significant potential for the treatment of type 2 diabetes mellitus (T2DM), hepatic steatosis, and cancer. However, the identification of tool compounds suitable to test the hypothesis in human trials has been challenging. An advanced series of spirocyclic ketone-containing ACC inhibitors recently reported by Pfizer were metabolized in vivo by ketone reduction, which complicated human pharmacology projections. We disclose that this metabolic reduction can be greatly attenuated through introduction of steric hindrance adjacent to the ketone carbonyl. Incorporation of weakly basic functionality improved solubility and led to the identification of 9 as a clinical candidate for the treatment of T2DM. Phase I clinical studies demonstrated dose-proportional increases in exposure, single-dose inhibition of de novo lipogenesis (DNL), and changes in indirect calorimetry consistent with increased whole-body fatty acid oxidation. This demonstration of target engagement validates the use of compound 9 to evaluate the role of DNL in human disease.


Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Hepatócitos/efeitos dos fármacos , Cetonas/metabolismo , Lipogênese/efeitos dos fármacos , Microssomos/efeitos dos fármacos , Acetil-CoA Carboxilase/metabolismo , Adulto , Animais , Área Sob a Curva , Células Cultivadas , Estudos Cross-Over , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Cães , Método Duplo-Cego , Hepatócitos/citologia , Humanos , Masculino , Malonil Coenzima A/metabolismo , Microssomos/metabolismo , Pessoa de Meia-Idade , Modelos Moleculares , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Relação Estrutura-Atividade , Adulto Jovem
19.
J Phys Chem B ; 118(38): 11129-36, 2014 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-25184622

RESUMO

Cyclic peptides are increasingly being recognized as valuable templates for drug discovery or design. To facilitate efforts in the structural characterization of cyclic peptides, we explore the use of pulse-field gradient experiments as a convenient and noninvasive approach for characterizing their diffusion properties in solution. We present diffusion coefficient measurements of five cyclic peptides, including dichC, SFTI-1, cVc1.1, kB1, and kB2. These peptides range in size from six to 29 amino acids and have various therapeutically interesting activities. We explore the use of internal standards, such as dioxane and acetonitrile, to evaluate the hydrodynamic radius from the diffusion coefficient, and show that 2,2-dimethyl-2-silapentane-5-sulfonic acid, a commonly used chemical shift reference, can be used as an internal standard to avoid spectral overlap issues and simplify data analysis. The experimentally measured hydrodynamic radii correlate with increasing molecular weight and in silico predictions. We further applied diffusion measurements to characterize the self-association of kB2 and showed that it forms oligomers in a concentration-dependent manner, which may be relevant to its mechanism of action. Diffusion coefficient measurements appear to have broad utility in cyclic peptide structural biology, allowing for the rapid characterization of their molecular shape in solution.


Assuntos
Espectroscopia de Ressonância Magnética/métodos , Peptídeos Cíclicos/química , Sequência de Aminoácidos , Difusão , Dados de Sequência Molecular
20.
Nat Chem Biol ; 10(8): 629-31, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24997604

RESUMO

We report that 4-(3-(benzyloxy)phenyl)-2-ethylsulfinyl-6-(trifluoromethyl)pyrimidine (BETP), which behaves as a positive allosteric modulator at the glucagon-like peptide-1 receptor (GLP-1R), covalently modifies cysteines 347 and 438 in GLP-1R. C347, located in intracellular loop 3 of GLP-1R, is critical to the activity of BETP and a structurally distinct GLP-1R ago-allosteric modulator, N-(tert-butyl)-6,7-dichloro-3-(methylsulfonyl)quinoxalin-2-amine. We further show that substitution of cysteine for phenylalanine 345 in the glucagon receptor is sufficient to confer sensitivity to BETP.


Assuntos
Pirimidinas/química , Receptores de Glucagon/metabolismo , Animais , Células CHO , Cricetulus , Cisteína/química , Peptídeo 1 Semelhante ao Glucagon/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1 , Humanos , Ligantes , Pirimidinas/metabolismo , Receptores de Glucagon/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA