RESUMEN
Protein tyrosine phosphatase 1B (PTP1B) is a member of the phosphotyrosine phosphatase family and plays an important role in the signal transduction of diabetes. Inhibition of PTP1B activity can increase insulin sensitivity and reduce blood sugar levels. Therefore, it is urgent to find compounds with novel structures that can inhibit PTP1B. This study designed imidazolidine-2,4-dione derivatives through the computer-aided drug design (CADD) strategy, and the Comp#10 showed outstanding inhibitory ability. (IC50 = 2.07 µM) and selectivity. The inhibitory mechanism at molecular level of Comp#10 on PTP1B was studied by molecular dynamics simulation. The results show that the catalytic region of PTP1B protein is more stable, which makes the catalytic sites unsuitable for exposure. Interestingly, the most obvious changes in the interaction between residues in the P-loop region (such as: His214, Cys215, and Ser216). In short, this study reported for the first time that imidazolidine-2,4-dione derivatives as novel PTP1B inhibitors had good inhibitory activity and selectivity, providing new ideas for the development of small molecule PTP1B inhibitors.
Asunto(s)
Imidazolidinas/síntesis química , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Algoritmos , Dominio Catalítico , Química Farmacéutica/métodos , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos , Humanos , Imidazolidinas/química , Concentración 50 Inhibidora , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Unión Proteica , Programas InformáticosRESUMEN
Over expressing in PTPN1 (encoding Protein tyrosine phosphatase 1B, PTP1B), a protein tyrosine phosphatase (PTP) that plays an overall positive role in insulin signaling, is linked to the pathogenesis of diabetes and obesity. The relationship between PTP1B and human diseases exhibits PTP1B as the target to treat these diseases. In this article, small weight molecules of the imidazolidine series were screened from databases and optimized on silicon as the inhibitors of PTP1B based on the steric conformation and electronic configuration of thiazolidinedione (TZD) compounds. The top three candidates were tested using an in vitro biological assay after synthesis. Finally, we report a novel inhibitor, Compound 13, that specifically inhibits PTP1B over the closely related phosphatase Src homology 2 (SH2) domain-containing phosphatase 2 (SHP-2) at 80 µΜ. Its IC50 values are reported in this paper as well. This compound was further verified by computer analysis for its ability to combine the catalytic domains of PTP1B and SHP-2 by molecular dynamics (MD) simulations.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Simulación de Dinámica Molecular , Proteína Tirosina Fosfatasa no Receptora Tipo 11/antagonistas & inhibidores , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Secuencia de Aminoácidos , Aminoácidos/metabolismo , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/química , Humanos , Ligandos , Datos de Secuencia Molecular , Unión Proteica/efectos de los fármacos , Conformación Proteica , Proteína Tirosina Fosfatasa no Receptora Tipo 1/química , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/química , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Alineación de Secuencia , Silicio , Termodinámica , Interfaz Usuario-ComputadorRESUMEN
A series of novel L-tyrosine derivatives were designed, synthesized and assayed for their inhibitory activities on matrix metalloproteinase 2 (MMP-2) and histone deacetylase 8 (HDAC-8). The results showed that these L-tyrosine derivatives exhibited inhibitory profiles against MMP-2 and HDAC-8. The compounds 6h (IC(50)=0.013 ± 0.001 µM) and 6j (IC(50)=0.017 ± 0.001 µM) were equal potent MMP-2 inhibitors to the positive control NNGH (IC(50)=0.014 ± 0.001 µM). As for HDAC-8 inhibition, some of the hydroxamate compounds, such as 6d (IC(50)=3.6 ± 0.2 µM) and 6c (IC(50)=5.8 ± 0.5 µM), were equal potent to the positive control SAHA (IC(50)=1.6 ± 0.1 µM). Structure-activity relationships were also briefly discussed.
Asunto(s)
Metaloproteinasa 2 de la Matriz/metabolismo , Inhibidores de la Metaloproteinasa de la Matriz/química , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Proteínas Represoras/antagonistas & inhibidores , Tirosina/análogos & derivados , Tirosina/farmacología , Diseño de Fármacos , Histona Desacetilasas/metabolismo , Humanos , Concentración 50 Inhibidora , Inhibidores de la Metaloproteinasa de la Matriz/síntesis química , Modelos Moleculares , Proteínas Represoras/metabolismo , Tirosina/síntesis químicaRESUMEN
BACKGROUND: The Peroxisome Proliferator-Activated Receptors (PPARs) are ligandactivated transcription factors belonging to the nuclear receptor family. The roles of PPARα in fatty acid oxidation and PPARγ in adipocyte differentiation and lipid storage have been widely characterized. Compounds with dual PPARα/γ activity have been proposed, combining the benefits of insulin sensitization and lipid lowering into one drug, allowing a single drug to reduce hyperglycemia and hyperlipidemia while preventing the development of cardiovascular complications. METHODS: The new PPARα/γ agonists were screened through virtual screening of pharmacophores and molecular dynamics simulations. First, in the article, the constructed pharmacophore was used to screen the Ligand Expo Components-pub database to obtain the common structural characteristics of representative PPARα/γ agonist ligands. Then, the accepted ligand structure was modified and replaced to obtain 12 new compounds. Using molecular docking, ADMET and molecular dynamics simulation methods to screen the designed 12 ligands, analyze their docking scores when they bind to the PPARα/γ dual targets, their stability and pharmacological properties when they bind to the PPARα/γ dual targets. RESULTS: We performed pharmacophore-based virtual screening for 22949 molecules in Ligand Expo Components-pub database. The compounds that were superior to the original ligand were performed structural analysis and modification, and a series of compounds with novel structures were designed. Using precise docking, ADMET prediction and molecular dynamics methods to screen and verify newly designed compounds, and the above compounds show higher docking scores and lower side effects. CONCLUSION: 9 new PPARα/γ agonists were obtained by pharmacophore modeling, docking analysis and molecular dynamics simulation.
Asunto(s)
Simulación de Dinámica Molecular , PPAR alfa , Ligandos , Lípidos , Simulación del Acoplamiento Molecular , PPAR alfa/agonistas , PPAR gamma/agonistasRESUMEN
The title compound, C(16)H(20)O(4), was obtained unintentionally as the byproduct of an attempted synthesis of methyl 3-(cyclo-propyl-meth-oxy)-4-hy-droxy-benzoate. In the crystal, the mol-ecules are linked by inter-molecular C-Hâ¯O inter-actions.
RESUMEN
PPARα and PPARγ play important roles in regulating glucose and lipid metabolism. In recent years, the development of dual PPAR agonists has become a hot topic in the field of anti-diabetic medicinal chemistry. The dual PPARα/γ agonists can both improve metabolism and reduce side effects caused by single drugs, and has become a promising strategy for designing effective drugs for the treatment of type 2 diabetes. In this study, by means of virtual screening, molecular docking and ADMET prediction technology, a representative compound with higher docking score, lower toxicity than original ligands was gained from the Ligand Expo Components database. It was observed through MD simulation that the representative compound not only has the function of activating the PPARα target and the PPARγ target, but also show a more favorable binding mode when the representative compound binds to the two receptors compared to the original ligands. Our results provided an approach to rapidly find novel PPARα/γ dual agonists for the treatment of type 2 diabetes mellitus (T2DM).This paper explores novel compounds targeting PPARα/γ dual agonists by using molecular docking, ADMET prediction, and molecular dynamics simulation methods. The specific flowchart is as follows: HighlightsThe results show that the skeleton of compound M80 is not only similar to Saroglitazar but also higher than that of Saroglitazar in activity.This study explained the binding modes of saroglitazar-PPARα/γ complexes and provided structure reference for the research and development of novel PPARα/γ dual agonists.
Asunto(s)
Diabetes Mellitus Tipo 2 , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Humanos , Ligandos , Simulación del Acoplamiento Molecular , PPAR alfa , PPAR gammaRESUMEN
Owing to its unique function in assisting the release of newly formed virus particles from the surface of an infected cell, neuraminidase, an antigenic glycoprotein enzyme, is a main target for drug design against influenza viruses. The group-1 neuraminidase of influenza virus possesses a 150-cavity, which is adjacent to the active pocket, and which renders conformational change from the 'open' form to the 'closed' form when the enzyme is binding with a ligand. Using AutoGrow evolutionary algorithm, one very unique fragment is screened out from the fragment databases by exploiting additional interactions with the 150-cavity. Subsequently, three derivatives were constructed by linking the unique fragment to oseltamivir at its three different sites. The three derivatives thus formed show much stronger inhibition power than oseltamivir, and hence may become excellent candidates for developing new and more powerful drugs for treating influenza. Or at the very least, the findings may stimulate new strategy or provide useful insights for working on the target vitally important to the health of human beings.
Asunto(s)
Antivirales/farmacología , Inhibidores Enzimáticos/farmacología , Proteína HN/efectos de los fármacos , Orthomyxoviridae/enzimología , Oseltamivir/análogos & derivados , Proteína HN/química , Humanos , Orthomyxoviridae/efectos de los fármacos , Conformación ProteicaRESUMEN
A tetramethylpyrazine analogue, CXC195, was synthesized by the Boekelheide reaction, in which the second methyl group of tetramethylpyrazine (TMP) was replaced with (4,4'-fluorine) diphenyl-methyl-1-piperazidine, the active group of flunarizine. We have observed protective effects of CXC195 on vascular endothelial cell survival under oxidative stress in previous study. The aim of the present study was to investigate the effects of CXC195 against apoptosis induced by hydrogen peroxide in human umbilical vein endothelial cells (HUVECs). Accordingly, a biochemical approach to elucidate the apoptotic signal pathways was attempted. HUVECs were exposed to 150 muM H(2)O(2) for 12 h, resulting in an increase of apoptotic cells assessed by the nuclear staining assay and flow cytometry. Mitochondrial membrane potential was detected by retention of rhodamine123. The concentration of free intracellular calcium was determined by fura-2/AM fluorometry. Co-incubation with CXC195 reduced the percentage of apoptotic cells and inhibited the loss of mitochondrial membrane potential and intracellular calcium overload induced by H(2)O(2). Induction of p53, the activation of caspase-3 by H(2)O(2) which accompanying downregulation of bcl-2, was blocked by CXC195. In addition, CXC195 clearly improved phosphorylation levels of the antiapoptotic extracellular signal-regulated kinase-1/2 (ERK1/2) in cells undergoing oxidative damage. Moreover, CXC195 showed stronger effects on inhibition of apoptotic cells and loss of mitochondrial membrane potential and activation of phosphorylated ERK1/2 than TMP. These results suggest that CXC195 prevents reactive oxygen species-induced apoptosis through inhibition of the mitochondria-dependent caspase-3 pathway and ERK pathway to show a better beneficial effect in protecting endothelial cells than TMP.
Asunto(s)
Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Calcio/metabolismo , Medicamentos Herbarios Chinos/farmacología , Células Endoteliales/efectos de los fármacos , Ligusticum/química , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Piperazinas/farmacología , Pirazinas/farmacología , Antioxidantes/síntesis química , Caspasa 3/metabolismo , Línea Celular , Regulación hacia Abajo , Células Endoteliales/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Citometría de Flujo , Humanos , Peróxido de Hidrógeno/farmacología , Estrés Oxidativo/efectos de los fármacos , Fosforilación , Fitoterapia , Piperazinas/síntesis química , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Pirazinas/síntesis química , Proteína p53 Supresora de Tumor/metabolismo , Venas UmbilicalesRESUMEN
In the title compound, C(10)H(10)N(2)O(3), the dihedral angle between the benzene and imidazolidine rings is 6.0â (4)°, consistent with an essentially planar mol-ecule. In the crystal, inter-molecular N-Hâ¯O hydrogen bonding between centrosymmetrically related mol-ecules leads to loosely associated dimeric aggregates. These are connected into a three-dimensional network by C-Hâ¯O inter-actions, as well as π-π inter-actions [centroid-centroid distances = 3.705â (3) and 3.622â (3)â Å] between the imidazolidine and benzene rings.
RESUMEN
In the title compound, C(12)H(14)O(4), the dihedral angle between the benzene ring and the cyclo-propyl ring is 60.3â (4)°. In the crystal structure, mol-ecules are linked by inter-molecular O-Hâ¯O hydrogen bonds into chains running parallel to [101].
RESUMEN
In the title mol-ecule, C(11)H(12)N(2)O(4), the dihedral angle between the benzene ring and imidazolidine ring is 7.1â (5)°. In the crystal structure, the hy-droxy groups are involved in the formation of inter-molecular O-Hâ¯O hydrogen bonds, which link the mol-ecules related by translation into C(2) chains along the b axis.
RESUMEN
In the title compound, C(17)H(14)BrClN(4)O(2), the pyrazole ring is almost coplanar with the benzene ring [dihedral angle = 0.5â (2)°], whereas the pyrazole ring is close to perpendicular to the 3-chloro-pyridine ring [dihedral angle = 73.7â (2)°]. An intra-molecular C-Hâ¯O hydrogen bond occurs. The dominant inter-action in the crystal packing is an N-Hâ¯N hydrogen bond, which generates a chain along the c axis. Weak inter-molecular C-Hâ¯O and C-Hâ¯N contacts are also observed.
RESUMEN
Peroxisome proliferator-activated receptors (PPARs) are considered important targets for the treatment of Type 2 diabetes (T2DM). To accelerate the discovery of PPAR α/γ dual agonists, the comparative molecular field analysis (CoMFA) were performed for PPARα and PPARγ, respectively. Based on the molecular alignment, highly predictive CoMFA model for PPARα was obtained with a cross-validated q2 value of 0.741 and a conventional r2 of 0.975 in the non-cross-validated partial least-squares (PLS) analysis, while the CoMFA model for PPARγ with a better predictive ability was shown with q2 and r2 values of 0.557 and 0.996, respectively. Contour maps derived from the 3D-QSAR models provided information on main factors towards the activity. Then, we carried out structural optimization and designed several new compounds to improve the predicted biological activity. To investigate the binding modes of the predicted compounds in the active site of PPARα/γ, a molecular docking simulation was carried out. Molecular dynamic (MD) simulations indicated that the predicted ligands were stable in the active site of PPARα/γ. Therefore, combination of the CoMFA and structure-based drug design results could be used for further structural alteration and synthesis and development of novel and potent dual agonists. AbbreviationsDMdiabetes mellitusT2DMtype 2 diabetesPPARsperoxisome proliferator-activated receptorsLBDDligand based drug design3D-QSARthree-dimensional quantitative structure activity relationshipCoMFAcomparative molecular field analysisPLSpartial least squareLOOleave-one-outq2cross-validated correlation coefficientONCoptimal number of principal componentsr2non-cross-validated correlation coefficientSEEstandard error of estimateFthe Fischer ratior2predpredictive correlation coefficientDBDDNA binding domainMDmolecular dynamicsRMSDroot-mean-square deviationRMSFroot mean square fluctuationsCommunicated by Ramaswamy H. Sarma.
Asunto(s)
PPAR alfa/agonistas , PPAR gamma/agonistas , Relación Estructura-Actividad Cuantitativa , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica MolecularRESUMEN
The therapeutic potential of PPARs antagonists extends beyond diabetes. PPARs antagonists represent a new drug class that holds promise as a broadly applicable therapeutic approach for cancer treatment. Thus, there is a strong need to develop a rational design strategy for creating PPARs antagonists. In this study, three-dimensional quantitative structure-activity relationship (3D-QSAR) models of PPARα receptor (CoMFA-1, q 2 = 0.636, r 2 = 0.953; CoMSIA-1, q 2 = 0.779, r 2 = 0.999) and PPARδ receptor (CoMFA-2, q 2 = 0.624, r 2 = 0.906; CoMSIA-2, q 2 = 0.627, r 2 = 0.959) were successfully constructed using 35 triazolone ring derivatives. Contour map analysis revealed that the electrostatic and hydrophobic fields played vital roles in the bioactivity of dual antagonists. Molecular docking studies suggested that the hydrogen bonding, electrostatic and hydrophobic interactions all influenced the binding of receptor-ligand complex. Based on the information obtained above, we designed a series of compounds. The docking results were mutually validated with 3D-QSAR results. Three-dimensional-QSAR and absorption, distribution, metabolism, excretion and toxicity (ADMET) predictions indicated that 19 newly designed compounds possessed excellent biological activity and physicochemical properties. In summary, this research could provide theoretical guidance for the structural optimization of novel PPARα and δ dual antagonists. Communicated by Ramaswamy H. Sarma.
Asunto(s)
PPAR delta , Relación Estructura-Actividad Cuantitativa , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , PPAR alfaRESUMEN
Communicated by Ramaswamy H. Sarma.
Asunto(s)
Fosfatidilinositol 3-Quinasas , Fosfatidilinositol 3-Quinasa Clase I , Inhibidores de las Quinasa Fosfoinosítidos-3RESUMEN
A series of novel acylpiperazinyl Ligustrazine derivatives was designed, synthesized, and their protective effects on damaged ECV-304 cells and antiplatelet aggregation activities were evaluated. The results showed that compound E33 displayed most potential protective effects on the ECV-304 cells damaged by hydrogen peroxide, and compound E1 was found to be the most active antiplatelet aggregation agent. Structure-activity relationships were briefly discussed.
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Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/farmacología , Pirazinas/síntesis química , Pirazinas/farmacología , Células Cultivadas , Diseño de Fármacos , Células Endoteliales/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Relación Estructura-ActividadRESUMEN
PPARα and PPARγ play an important role in regulating glucose and lipid metabolism. The single and selective PPARα or PPARγ agonists have caused several side effects such as edema, weight gain and cardiac failure. In the recent years, the dual PPARs agonist development has become a hot topic in the antidiabetic medicinal chemistry field. In this paper, the compound CHEMBL230490 were gained from CHEMBL database, by means of complex-based pharmacophore (CBP) virtual screening, molecular docking, ADMET prediction and molecular dynamics (MD) simulations. The compound CHEMBL230490 not only displayed higher binding scores and better binding modes with the active site of PPARα a/γ, but also had more favorable the pharmacokinetic properties and toxicity evaluated by ADMET prediction. The representative compound CHEMBL230490 was performed to MDs for studying a stable binding conformation. The results indicated that the CHEMBL230490 might be a potential antidiabetic lead compound. The research provided a valuable approach in developing novel PPARα/γ dual agonists for the treatment of type 2 diabetes mellitus (T2DM).
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/química , PPAR alfa/agonistas , PPAR gamma/agonistas , Bibliotecas de Moléculas Pequeñas/química , Evaluación Preclínica de Medicamentos , Humanos , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Estructura Molecular , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/uso terapéuticoRESUMEN
BACKGROUND: Phosphoinositide-3-kinase Delta (PI3Kδ) plays a key role in B-cell signal transduction and inhibition of PI3Kδ is confirmed to have clinical benefit in certain types of activation of B-cell malignancies. Virtual screening techniques have been used to discover new molecules for developing novel PI3Kδ inhibitors with little side effects. METHOD: Computer aided drug design method were used to rapidly screen optimal PI3Kδ inhibitors from the Asinex database. Virtual screening based molecular docking was performed to find novel and potential lead compound targeting PI3Kδ, at first. Subsequently, drug likeness studies were carried out on the retrieved hits to evaluate and analyze their drug like properties such as absorption, distribution, metabolism, excretion, and toxicity (ADMET) for toxicity prediction. Three least toxic compounds were selected for the molecular dynamics (MD) simulations for 30 ns in order to validate its stability inside the active site of PI3Kδ receptor. RESULTS: Based on the present in silico analysis, two molecules have been identified which occupied the same binding pocket confirming the selection of active site. ASN 16296138 (Glide score: -12.175 kcal/mol, cdocker binding energy: -42.975 kcal/mol and ΔGbind value: -90.457 kcal/mol) and BAS 00227397 (Glide score: -10.988 kcal/mol, cdocker binding energy: -39.3376 kcal/mol and ΔGbind value: -81.953 kcal/mol) showed docking affinities comparatively much stronger than those of already reported known inhibitors against PI3Kδ. These two ligand's behaviors also showed consistency during the simulation of protein-ligand complexes for 30000 ps respectively, which is indicative of its stability in the receptor pocket. CONCLUSION: Compound ASN 16296138 and BAS 00227397 are potential candidates for experimental validation of biological activity against PI3Kδ in future drug discovery studies. This study smoothes the path for the development of novel leads with improved binding properties, high drug likeness, and low toxicity to humans for the treatment of cancer.
Asunto(s)
Diseño Asistido por Computadora , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Inhibidores de Proteínas Quinasas/química , Bibliotecas de Moléculas Pequeñas/química , Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Humanos , Ligandos , Estructura Molecular , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Piel/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , TermodinámicaRESUMEN
Sulfonamide hydroxamates were designed and synthesized as efficient matrix metalloproteinase (MMP) inhibitors since the discovery of CGS 27023A in 1994. The sulfonamide group was incorporated in the inhibitor to improve the enzyme-inhibitor binding, not only by forming hydrogen bonds to the enzyme but also by properly directing the hydrophobic substituent to the S1' pocket and enabling it to plunge in deeply. Some researchers even presumed that the sulfonamide group, together with the zinc binding group (ZBG), coordinated the zinc ion within the MMP active site. This review will illustrate the role of the sulfonamide group in MMP inhibitors.
Asunto(s)
Inhibidores de la Metaloproteinasa de la Matriz , Metaloproteinasas de la Matriz/química , Inhibidores de Proteasas/farmacología , Sulfonamidas/farmacología , Animales , Sitios de Unión , Humanos , Enlace de Hidrógeno , Modelos Moleculares , Inhibidores de Proteasas/química , Sulfonamidas/químicaRESUMEN
Matrix metalloproteinases (MMPs) play an important role in many physiological and pathological processes. MMP inhibitors have been considered as potential therapeutics for neoplasitc, rheumatic and cardiovascular diseases. Our group and others have been developing pyrrolidine scaffold-based MMP inhibitors for a number of years, and numerous compounds have been reported in the literature. These compounds can be classified as sulfonamide pyrrolidine derivatives, proline-containing peptidomimetics and acyl pyrrolidine derivatives. These synthetic MMP inhibitors show low nanomolar activity for some MMP subclasses, thus confirming pyrrolidine ring an excellent scaffold from which to design MMP inhibitors. This review will focus primarily on the structure, activity and selectivity profiles of pyrrolidine scaffold-based MMP inhibitors.