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Current Computer-aided Drug Design 2020Glycogen synthase kinase-3 (GSK3) is associated with various key biological processes and has been considered as an important therapeutic target for the treatment of...
Theoretical Studies on the Selectivity Mechanisms of Glycogen Synthase Kinase 3β (GSK3β) with Pyrazine ATP-competitive Inhibitors by 3DQSAR, Molecular Docking, Molecular Dynamics Simulation and Free Energy Calculations.
BACKGROUND
Glycogen synthase kinase-3 (GSK3) is associated with various key biological processes and has been considered as an important therapeutic target for the treatment of many diseases. Great efforts have been made on the development of GSK3 inhibitors, especially ATP-competitive GSK3β inhibitor, but it is still a great challenge to develop selective GSK3β inhibitors because of the high sequence homology with other kinases.
OBJECTIVE
In order to reveal the selectivity mechanisms of GSK3β inhibition at the molecular level, a series of ATP-competitive GSK3β inhibitor was analyzed by a systematic computational method, combining 3DQSAR, molecular docking, molecular dynamic simulations and free energy calculations.
METHODS
Firstly, 3D-QSAR with CoMFA was built to explore the general structure activity relationships. Secondly, CDOCKER and Flexible docking were employed to predicted the reasonable docking poses of all studied inhibitors. And then, both GSK3β and CDK2 complexes were selected to conduct molecular dynamics simulations. Finally, the free energy calculations were employed to find the key selective-residues.
RESULTS
CoMFA model suggested the steric, hydrophobic fields play key roles in the bioactivities of inhibitors, and the binding mechanisms were well analyzed through molecular docking. The binding free energies predicted are in good agreement with the experimental bioactivities and the free energy calculations showed that the binding of GSK3β/inhibitors was mainly contributed from hydrogen bonding and hydrophobic interaction.
CONCLUSION
Some key residues for selective binding were highlighted, which may afford important guidance for the rational design of novel ATP-competitive GSK3β inhibitors.
Topics: Adenosine Triphosphate; Binding, Competitive; Drug Design; Glycogen Synthase Kinase 3 beta; Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Models, Molecular; Molecular Docking Simulation; Molecular Dynamics Simulation; Protein Kinase Inhibitors; Pyrazines; Quantitative Structure-Activity Relationship
PubMed: 31284868
DOI: 10.2174/1573409915666190708102459 -
Molecules (Basel, Switzerland) Nov 20182,3-Diphenylated quinoxaline, pyrido[2,3-]pyrazine and 8-bromopyrido[3,4-]pyrazine were halogenated in deprotometalation-trapping reactions using mixed...
2,3-Diphenylated quinoxaline, pyrido[2,3-]pyrazine and 8-bromopyrido[3,4-]pyrazine were halogenated in deprotometalation-trapping reactions using mixed 2,2,6,6-tetramethyl piperidino-based lithium-zinc combinations in tetrahydrofuran. The 2,3-diphenylated 5-iodo- quinoxaline, 8-iodopyrido[2,3-]pyrazine and 8-bromo-7-iodopyrido[3,4-]pyrazine thus obtained were subjected to palladium-catalyzed couplings with arylboronic acids or anilines, and possible subsequent cyclizations to afford the corresponding pyrazino[2,3-]carbazole, pyrazino[2',3':5,6] pyrido[4,3-]indole and pyrazino[2',3':4,5]pyrido[2,3-]indole, respectively. 8-Iodopyrido[2,3-] pyrazine was subjected either to a copper-catalyzed C-N bond formation with azoles, or to direct substitution to introduce alkylamino, benzylamino, hydrazine and aryloxy groups at the 8 position. The 8-hydrazino product was converted into aryl hydrazones. Most of the compounds were evaluated for their biological properties (antiproliferative activity in A2058 melanoma cells and disease-relevant kinase inhibition).
Topics: Carbazoles; Carbolines; Molecular Structure; Oxidative Coupling; Palladium; Pyrazines; Quinoxalines
PubMed: 30428591
DOI: 10.3390/molecules23112961 -
Molecules (Basel, Switzerland) Dec 2022Marine Coelenterazine is one of the most well-known chemi-/bioluminescent systems, and in which reaction the chemi-/bioluminophore (Coelenteramide) is generated and...
Marine Coelenterazine is one of the most well-known chemi-/bioluminescent systems, and in which reaction the chemi-/bioluminophore (Coelenteramide) is generated and chemiexcited to singlet excited states (leading to light emission). Recent studies have shown that the bromination of compounds associated with the marine Coelenterazine system can provide them with new properties, such as anticancer activity and enhanced emission. Given this, our objective is to characterize the photophysical properties of a previously reported brominated Coelenteramide analog, by employing a combined experimental and theoretical approach. To better analyze the potential halogen effect, we have also synthesized and characterized, for the first time, two new fluorinated and chlorinated Coelenteramide analogs. These compounds show similar emission spectra in aqueous solution, but with different fluorescence quantum yields, in a trend that can be correlated with the heavy-atom effect (F > Cl > Br). A blue shift in emission in other solvents is also verified with the F−Cl−Br trend. More relevantly, the fluorescence quantum yield of the brominated analog is particularly sensitive to changes in solvent, which indicates that this compound has potential use as a microenvironment fluorescence probe. Theoretical calculations indicate that the observed excited state transitions result from local excitations involving the pyrazine ring. The obtained information should be useful for the further exploration of halogenated Coelenteramides and their luminescent properties.
Topics: Pyrazines; Luminescence; Fluorescence; Solvents
PubMed: 36558008
DOI: 10.3390/molecules27248875 -
Leukemia & Lymphoma May 2009Rapid development of the small molecule proteasome inhibitor bortezomib has yielded important clinical benefit for patients with multiple myeloma. Early phase clinical... (Review)
Review
Rapid development of the small molecule proteasome inhibitor bortezomib has yielded important clinical benefit for patients with multiple myeloma. Early phase clinical trials suggest the agent has similar efficacy in Waldenströms Macroglobulinemia. Optimization of bortezomib-based therapy, though, requires an understanding of the various challenges associated with use of the drug. This review highlights the rationale for bortezomib therapy in patients with multiple myeloma and Waldenströms Macroglobulinemia, mechanisms of bortezomib resistance, important therapy-related side effects, and new directions for the use of proteasome inhibitors in these disorders.
Topics: Antineoplastic Agents; Boronic Acids; Bortezomib; Drug Resistance, Neoplasm; Humans; Multiple Myeloma; Protease Inhibitors; Pyrazines; Waldenstrom Macroglobulinemia
PubMed: 19452315
DOI: 10.1080/10428190902866732 -
Induced intra- and intermolecular template switching as a therapeutic mechanism against RNA viruses.Molecular Cell Nov 2021Viral RNA-dependent RNA polymerases (RdRps) are a target for broad-spectrum antiviral therapeutic agents. Recently, we demonstrated that incorporation of the T-1106...
Viral RNA-dependent RNA polymerases (RdRps) are a target for broad-spectrum antiviral therapeutic agents. Recently, we demonstrated that incorporation of the T-1106 triphosphate, a pyrazine-carboxamide ribonucleotide, into nascent RNA increases pausing and backtracking by the poliovirus RdRp. Here, by monitoring enterovirus A-71 RdRp dynamics during RNA synthesis using magnetic tweezers, we identify the "backtracked" state as an intermediate used by the RdRp for copy-back RNA synthesis and homologous recombination. Cell-based assays and RNA sequencing (RNA-seq) experiments further demonstrate that the pyrazine-carboxamide ribonucleotide stimulates these processes during infection. These results suggest that pyrazine-carboxamide ribonucleotides do not induce lethal mutagenesis or chain termination but function by promoting template switching and formation of defective viral genomes. We conclude that RdRp-catalyzed intra- and intermolecular template switching can be induced by pyrazine-carboxamide ribonucleotides, defining an additional mechanistic class of antiviral ribonucleotides with potential for broad-spectrum activity.
Topics: Animals; Antiviral Agents; Catalysis; Cells, Cultured; Genetic Techniques; Genome; Genome, Viral; Homologous Recombination; Humans; Kinetics; Mice; Mice, Transgenic; Molecular Dynamics Simulation; Mutagenesis; Nucleotides; Protein Conformation; Pyrazines; RNA; RNA Viruses; RNA, Viral; RNA-Dependent RNA Polymerase; RNA-Seq; Recombination, Genetic; Ribonucleotides; Transgenes; Virulence
PubMed: 34687604
DOI: 10.1016/j.molcel.2021.10.003 -
The Journal of Infectious Diseases Apr 2016Rabies is a fatal encephalitis caused by rabies virus (RABV), and no antiviral drugs for RABV are currently available. We report for the first time the efficacy of...
Rabies is a fatal encephalitis caused by rabies virus (RABV), and no antiviral drugs for RABV are currently available. We report for the first time the efficacy of favipiravir (T-705) against RABV in vitro and in vivo. T-705 produced a significant, 3-4 log10 reduction in the multiplication of street and fixed RABV strains in mouse neuroblastoma Neuro-2a cells, with half-maximal inhibitory concentrations of 32.4 µM and 44.3 µM, respectively. T-705 significantly improved morbidity and mortality among RABV-infected mice when orally administered at a dose of 300 mg/kg/day for 7 days, beginning 1 hour after inoculation. T-705 significantly reduced the rate of virus positivity in the brain. Furthermore, the effectiveness of T-705 was comparable to that of equine rabies virus immunoglobulin for postexposure prophylaxis. Collectively, our results suggest that T-705 is active against RABV and may serve as a potential alternative to rabies immunoglobulin in rabies postexposure prophylaxis.
Topics: Amides; Animals; Antiviral Agents; Cell Line; Disease Models, Animal; Mice; Post-Exposure Prophylaxis; Pyrazines; Rabies; Treatment Outcome; Viral Load
PubMed: 26655300
DOI: 10.1093/infdis/jiv586 -
Haematologica Oct 2007
Topics: Animals; Boronic Acids; Bortezomib; Humans; Neurotoxicity Syndromes; Pain; Pyrazines
PubMed: 18024368
DOI: 10.3324/haematol.11752 -
Haematologica Jul 2024Sovleplenib (HMPL-523) is a selective spleen tyrosine kinase (Syk) inhibitor with anti-tumor activity in preclinical models of B-cell malignancy. We conducted a...
Sovleplenib (HMPL-523) is a selective spleen tyrosine kinase (Syk) inhibitor with anti-tumor activity in preclinical models of B-cell malignancy. We conducted a dose-escalation and dose-expansion phase I study of sovleplenib in patients with relapsed/ refractory mature B-cell tumors. Dose escalation followed a 3+3 design; patients received oral sovleplenib (200-800 mg once daily [q.d.] or 200 mg twice daily [b.i.d.], 28-day cycles). During dose expansion, patients were enrolled into four cohorts per lymphoma classification and treated at the recommended phase II dose (RP2D) (clinicaltrials gov. Identifier: NCT02857998). Overall, 134 Chinese patients were enrolled (dose escalation, N=27; dose expansion, N=107). Five patients experienced dose-limiting toxicities: one each of amylase increased (200 mg q.d.), febrile neutropenia (800 mg q.d.), renal failure (800 mg q.d.), hyperuricemia and blood creatine phosphokinase increased (200 mg b.i.d.) and blood bilirubin increased and pneumonia (200 mg b.i.d.). RP2D was determined as 600 mg (>65 kg) or 400 mg (≤65 kg) q.d.. The primary efficacy end point of independent review committee-assessed objective response rate in indolent B-cell lymphoma was 50.8% (95% confidence interval: 37.5- 64.1) in 59 evaluable patients at RP2D (follicular lymphoma: 60.5%, marginal zone lymphoma: 28.6%, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, 0%). The most common (≥10% patients) grade ≥3 treatment-related adverse events in the dose-expansion phase were decreased neutrophil count (29.9%), pneumonia (12.1%) and decreased white blood cell count (11.2%). Pharmacokinetic exposures increased dose-proportionally with ascending dose levels from 200-800 mg, without observed saturation. Sovleplenib showed anti-tumor activity in relapsed/refractory B-cell lymphoma with acceptable safety. Further studies are warranted.
Topics: Humans; Middle Aged; Male; Female; Syk Kinase; Aged; Adult; Lymphoma, B-Cell; Protein Kinase Inhibitors; Young Adult; Aged, 80 and over; Treatment Outcome; Drug Resistance, Neoplasm; Maximum Tolerated Dose; Pyrazines; Recurrence; Antineoplastic Agents; Indazoles; Morpholines
PubMed: 38235512
DOI: 10.3324/haematol.2022.282401 -
Anticancer Research 2006Chemotherapy is the commonly accepted standard therapy for most types of brain tumor, especially in medulloblastoma, primitive neuroectodermal tumor and astrocytoma....
BACKGROUND
Chemotherapy is the commonly accepted standard therapy for most types of brain tumor, especially in medulloblastoma, primitive neuroectodermal tumor and astrocytoma. However, no efficient therapy has been established to date for glioblastoma multiforme. The aim of the present study was to analyze the activity of bortezomib in glioblastoma cell lines in comparison with that in a pediatric acute lymphoblastic leukemia cell line.
MATERIALS AND METHODS
Glioblastoma multiforme T98G, glioblastoma-astrocytoma U373M and T-lineage acute lymphoblastic leukemia CCRF-CEM cell lines were used. Proteasome inhibitor, bortezomib and 14 other anticancer drugs were tested using the MTT assay.
RESULTS
Compared to the acute lymphoblastic cell line, both glioblastoma cell lines showed relatively good sensitivity to bortezomib, as well as to cisplatin, carboplatin, etoposide and actinomycin-D. The lines showed intermediate sensitivity to thiotepa and daunorubicin, but were highly resistant to first-line drugs used in the therapy of acute lymphoblastic leukemia, such as prednisolone, L-asparaginase, vincristine, doxorubicin and cytarabine. Bortezomib, which is not a substrate for PGP and MRP1, did not show cross resistance to drugs transported by these proteins.
CONCLUSION
Our results support the necessity for further research on the role of bortezomib in the therapy of glioblastoma.
Topics: Antineoplastic Agents; Boronic Acids; Bortezomib; Brain Neoplasms; Cell Line, Tumor; Glioblastoma; Humans; Pyrazines
PubMed: 17201170
DOI: No ID Found -
Chemical & Pharmaceutical Bulletin Feb 20022-Amino-3-benzyl-5-(p-hydroxyphenyl)pyrazine (2), a precursor of Watasenia preluciferin (coelenterazine) (1), is widely distributed in marine bioluminescent animals. It...
2-Amino-3-benzyl-5-(p-hydroxyphenyl)pyrazine (2), a precursor of Watasenia preluciferin (coelenterazine) (1), is widely distributed in marine bioluminescent animals. It was prepared from p-hydroxyphenylglyoxal aldoxime (5) in two steps; by condensation with or-aminophenylpropiononitrile in the presence of TiCl4 in pyridine, followed by reduction of the resulting N-oxide (6) with Zn-AcOH in CH2Cl2 and produced 2, with an 89% overall yield. This procedure was linked with the facile one-step preluciferin synthesis reported in the previous paper. Thus, Watasenia preluciferin (1), frequently required for various chemiluminescent and bioluminescent studies, was coveniently synthesized in three steps from 5, with a 56% overall yield, overcoming the difficulty of obtaining it from natural sources.
Topics: Imidazoles; Luminescent Measurements; Molecular Conformation; Pyrazines
PubMed: 11848229
DOI: 10.1248/cpb.50.301