scholarly journals Fragment-Based Lead Generation of 5-Phenyl-1H-pyrazole-3-carboxamide Derivatives as Leads for Potent Factor Xia Inhibitors

Molecules ◽  
2018 ◽  
Vol 23 (8) ◽  
pp. 2002 ◽  
Author(s):  
Qunchao Wei ◽  
Zhichao Zheng ◽  
Shijun Zhang ◽  
Xuemin Zheng ◽  
Fancui Meng ◽  
...  
Keyword(s):  
Binding Mode ◽  
Lead Discovery ◽  
Inhibitory Potency ◽  
Efficient Manner ◽  
Factor Xia ◽  
Anticoagulant Drug ◽  
Lead Generation ◽  
Potent Factor ◽  
Major Target

FXIa is suggested as a major target for anticoagulant drug discovery because of reduced risk of bleeding. In this paper, we defined 5-phenyl-1H-pyrazole-3-carboxylic acid derivatives as privileged fragments for FXIa inhibitors’ lead discovery. After replacing the (E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylamide moiety in compound 3 with 5-(3-chlorophenyl)-1H-pyrazole-3-carboxamide, we traveled from FXIa inhibitor3 to a scaffold that fused the privileged fragments into a pharmacophore for FXIa inhibitors. Subsequently, we synthesized and assessed the FXIa inhibitory potency of a series of 5-phenyl-1H-pyrazole-3-carboxamide derivatives with different P1, P1′ and P2′moiety. Finally, the SAR of them was systematically investigated to afford the lead compound 7za (FXIa Ki = 90.37 nM, 1.5× aPTT in rabbit plasma = 43.33μM) which exhibited good in vitro inhibitory potency against FXIa and excellent in vitro coagulation activities. Furthermore, the binding mode of 7za with FXIa was studied and the results suggest that the 2-methylcyclopropanecarboxamide group of 7za makes 2 direct hydrogen bonds with Tyr58B and Thr35 in the FXIa backbone, making 7za binds to FXIa in a highly efficient manner.

Design, Synthesis, Molecular Docking and Biological Evaluation of 1-(benzo[d]thiazol-2-ylamino)(phenyl)methyl)naphthalen-2-ol Derivatives as Antiproliferative Agents

2019 ◽  
Vol 16 (10) ◽  
pp. 837-845
Author(s):  
Sandhya Jonnala ◽  
Bhaskar Nameta ◽  
Murthy Chavali ◽  
Rajashaker Bantu ◽  
Pallavi Choudante ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Inhibitory Activity ◽  
Chinese Hamster Ovary Cells ◽  
Chinese Hamster ◽  
Mouse Skin ◽  
Coupling Reaction ◽  
Binding Mode ◽  
Biological Evaluation ◽  
Design Synthesis

A class of 1-((benzo[d]thiazol-2-ylamino)(phenyl)methyl)naphthalen-2-ol derivatives (4a-t) has been synthesized in good yields through a three component coupling reaction. The newly synthesized compounds were evaluated for their in vitro antiproliferative activity against five cell lines such as DU145 (human prostate cancer), MDA-MB-B231 (human breast cancer), SKOV3 (human ovarian cancer), B16-F10 (mouse skin melanoma) and CHO-K1 (Chinese hamster ovary cells), a noncancerous cell line. In vitro inhibitory activity indicates that compounds 4a, 4b, 4c, 4d, 4g, 4j, and 4o exhibited potent anti-proliferative behavior. Among them, compounds 4g, 4j and 4o found to be the most active members exhibiting remarkable growth inhibitory activity. Molecular docking facilitates to investigate the probable binding mode and key active site interactions in tubulins α and β proteins. The docking results are complementary to experimental results.

scholarly journals The Repurposed Drugs Suramin and Quinacrine Cooperatively Inhibit SARS-CoV-2 3CLpro In Vitro

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 873
Author(s):  
Raphael J. Eberle ◽  
Danilo S. Olivier ◽  
Marcos S. Amaral ◽  
Ian Gering ◽  
Dieter Willbold ◽  
...  
Keyword(s):  
Binding Mode ◽  
Drug Candidates ◽  
Main Protease ◽  
Ic50 Values ◽  
Repurposed Drugs ◽  
Antiparasitic Drugs ◽  
Inhibitory Potential ◽  
Dynamics Simulations ◽  
Micromolar Range

Since the first report of a new pneumonia disease in December 2019 (Wuhan, China) the WHO reported more than 148 million confirmed cases and 3.1 million losses globally up to now. The causative agent of COVID-19 (SARS-CoV-2) has spread worldwide, resulting in a pandemic of unprecedented magnitude. To date, several clinically safe and efficient vaccines (e.g., Pfizer-BioNTech, Moderna, Johnson & Johnson, and AstraZeneca COVID-19 vaccines) as well as drugs for emergency use have been approved. However, increasing numbers of SARS-Cov-2 variants make it imminent to identify an alternative way to treat SARS-CoV-2 infections. A well-known strategy to identify molecules with inhibitory potential against SARS-CoV-2 proteins is repurposing clinically developed drugs, e.g., antiparasitic drugs. The results described in this study demonstrated the inhibitory potential of quinacrine and suramin against SARS-CoV-2 main protease (3CLpro). Quinacrine and suramin molecules presented a competitive and noncompetitive inhibition mode, respectively, with IC50 values in the low micromolar range. Surface plasmon resonance (SPR) experiments demonstrated that quinacrine and suramin alone possessed a moderate or weak affinity with SARS-CoV-2 3CLpro but suramin binding increased quinacrine interaction by around a factor of eight. Using docking and molecular dynamics simulations, we identified a possible binding mode and the amino acids involved in these interactions. Our results suggested that suramin, in combination with quinacrine, showed promising synergistic efficacy to inhibit SARS-CoV-2 3CLpro. We suppose that the identification of effective, synergistic drug combinations could lead to the design of better treatments for the COVID-19 disease and repurposable drug candidates offer fast therapeutic breakthroughs, mainly in a pandemic moment.

scholarly journals Efficient Peptide-Mediated In Vitro Delivery of Cas9 RNP

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 878
Author(s):  
Oskar Gustafsson ◽  
Julia Rädler ◽  
Samantha Roudi ◽  
Tõnis Lehto ◽  
Mattias Hällbrink ◽  
...  
Keyword(s):  
Freeze Drying ◽  
Cell Penetrating Peptide ◽  
Wild Type ◽  
Efficient Manner ◽  
Editing Efficiency ◽  
Freeze Thaw ◽  
Enzyme Digest ◽  
Clinical Potential ◽  
Generation Sequencing

The toolbox for genetic engineering has quickly evolved from CRISPR/Cas9 to a myriad of different gene editors, each with promising properties and enormous clinical potential. However, a major challenge remains: delivering the CRISPR machinery to the nucleus of recipient cells in a nontoxic and efficient manner. In this article, we repurpose an RNA-delivering cell-penetrating peptide, PepFect14 (PF14), to deliver Cas9 ribonucleoprotein (RNP). The RNP-CPP complex achieved high editing rates, e.g., up to 80% in HEK293T cells, while being active at low nanomolar ranges without any apparent signs of toxicity. The editing efficiency was similar to or better compared to the commercially available reagents RNAiMAX and CRISPRMax. The efficiency was thoroughly evaluated in reporter cells and wild-type cells by restriction enzyme digest and next-generation sequencing. Furthermore, the CPP-Cas9-RNP complexes were demonstrated to withstand storage at different conditions, including freeze-thaw cycles and freeze-drying, without a loss in editing efficiency. This CPP-based delivery strategy complements existing technologies and further opens up new opportunities for Cas9 RNP delivery, which can likely be extended to other gene editors in the future.

scholarly journals Definition of the Binding Architecture to a Target Promoter of HP1043, the Essential Master Regulator of Helicobacter pylori

2021 ◽  
Vol 22 (15) ◽  
pp. 7848
Author(s):  
Annamaria Zannoni ◽  
Simone Pelliciari ◽  
Francesco Musiani ◽  
Federica Chiappori ◽  
Davide Roncarati ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Response Regulator ◽  
Consensus Sequence ◽  
Binding Mode ◽  
In Vitro Transcription ◽  
Target Sequence ◽  
Computational Alanine Scanning ◽  
Definition Of ◽  
Target Promoter

HP1043 is an essential orphan response regulator of Helicobacter pylori orchestrating multiple crucial cellular processes. Classified as a member of the OmpR/PhoB family of two-component systems, HP1043 exhibits a highly degenerate receiver domain and evolved to function independently of phosphorylation. Here, we investigated the HP1043 binding mode to a target sequence in the hp1227 promoter (Php1227). Scanning mutagenesis of HP1043 DNA-binding domain and consensus sequence led to the identification of residues relevant for the interaction of the protein with a target DNA. These determinants were used as restraints to guide a data-driven protein-DNA docking. Results suggested that, differently from most other response regulators of the same family, HP1043 binds in a head-to-head conformation to the Php1227 target promoter. HP1043 interacts with DNA largely through charged residues and contacts with both major and minor grooves of the DNA are required for a stable binding. Computational alanine scanning on molecular dynamics trajectory was performed to corroborate our findings. Additionally, in vitro transcription assays confirmed that HP1043 positively stimulates the activity of RNA polymerase.

scholarly journals Synthesis and Evaluation of Novel α-Aminoamides Containing Benzoheterocyclic Moiety for the Treatment of Pain

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1716
Author(s):  
Kun Tong ◽  
Ruotian Zhang ◽  
Fengzhi Ren ◽  
Tao Zhang ◽  
Junlin He ◽  
...  
Keyword(s):  
Ion Channels ◽  
Patch Clamp ◽  
Formalin Test ◽  
Sodium Ion ◽  
Inhibitory Potency ◽  
Voltage Gated ◽  
Patch Clamp Electrophysiology ◽  
Sodium Ion Channels

Novel α-aminoamide derivatives containing different benzoheterocyclics moiety were synthesized and evaluated as voltage-gated sodium ion channels blocks the treatment of pain. Compounds 6a, 6e, and 6f containing the benzofuran group displayed more potent in vivo analgesic activity than ralfinamide in both the formalin test and the writhing assay. Interestingly, they also exhibited potent in vitro anti-Nav1.7 and anti-Nav1.8 activity in the patch-clamp electrophysiology assay. Therefore, compounds 6a, 6e, and 6f, which have inhibitory potency for two pain-related Nav targets, could serve as new leads for the development of analgesic medicines.

scholarly journals Specificity of the HIV-1 Protease on Substrates Representing the Cleavage Site in the Proximal Zinc-Finger of HIV-1 Nucleocapsid Protein

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1092
Author(s):  
János András Mótyán ◽  
Márió Miczi ◽  
Stephen Oroszlan ◽  
József Tőzsér
Keyword(s):  
Amino Acid ◽  
Zinc Finger ◽  
Cleavage Site ◽  
Potential Role ◽  
Binding Mode ◽  
Interaction Energies ◽  
Vitro Assay ◽  
Hiv 1

To explore the sequence context-dependent nature of the human immunodeficiency virus type 1 (HIV-1) protease’s specificity and to provide a rationale for viral mutagenesis to study the potential role of the nucleocapsid (NC) processing in HIV-1 replication, synthetic oligopeptide substrates representing the wild-type and modified versions of the proximal cleavage site of HIV-1 NC were assayed as substrates of the HIV-1 protease (PR). The S1′ substrate binding site of HIV-1 PR was studied by an in vitro assay using KIVKCF↓NCGK decapeptides having amino acid substitutions of N17 residue of the cleavage site of the first zinc-finger domain, and in silico calculations were also performed to investigate amino acid preferences of S1′ site. Second site substitutions have also been designed to produce “revertant” substrates and convert a non-hydrolysable sequence (having glycine in place of N17) to a substrate. The specificity constants obtained for peptides containing non-charged P1′ substitutions correlated well with the residue volume, while the correlation with the calculated interaction energies showed the importance of hydrophobicity: interaction energies with polar residues were related to substantially lower specificity constants. Cleavable “revertants” showed one residue shift of cleavage position due to an alternative productive binding mode, and surprisingly, a double cleavage of a substrate was also observed. The results revealed the importance of alternative binding possibilities of substrates into the HIV-1 PR. The introduction of the “revertant” mutations into infectious virus clones may provide further insights into the potential role of NC processing in the early phase of the viral life-cycle.

scholarly journals Assessment of Galvanostatic Anodic Polarization to Accelerate the Corrosion of the Bioresorbable Magnesium Alloy WE43

2021 ◽  
Vol 11 (5) ◽  
pp. 2128
Author(s):  
Nils Wegner ◽  
Frank Walther
Keyword(s):  
Magnesium Alloy ◽  
Corrosion Rate ◽  
Dissolution Rate ◽  
Anodic Polarization ◽  
Technical Application ◽  
Efficient Manner ◽  
Corrosion Morphology ◽  
Application Range ◽  
Alloy We43

In the field of surgery, bioresorbable magnesium is considered a promising candidate. Its low corrosion resistance, which is disadvantageous for technical application, is advantageous for surgery since the implant fully degrades in the presence of the water-based body fluids, and after a defined time the regenerating bone takes over its function again. Therefore, knowledge of the corrosion behavior over several months is essential. For this reason, an in vitro short-time testing method is developed to accelerate the corrosion progress by galvanostatic anodic polarization without influencing the macroscopic corrosion morphology. The initial corrosion rate of the magnesium alloy WE43 is calculated by detection of the hydrogen volume produced in an immersion test. In a corresponding experimental setup, a galvanostatic anodic polarization is applied with a three-electrode system. The application range for the polarization is determined based on the corrosion current density from potentiodynamic polarization. To correlate the initial corrosion rate, and accelerated dissolution rate, the corrosion morphologies of both test strategies are characterized by microscopy images, as well as energy dispersive X-ray spectroscopy and Fourier-transform infrared spectroscopy. The results demonstrate that the dissolution rate can be increased in the order of decades with the limitation of a changed corrosion morphology with increasing polarization. With this approach, it is possible to characterize and exclude new unsuitable magnesium alloys in a time-efficient manner before they are used in subsequent preclinical studies.

Inhibition of Adenosine Triphosphatases in Vitro by Silver Nitrate and Silver Sulfadiazine

1984 ◽  
Vol 3 (1) ◽  
pp. 37-42 ◽  
Author(s):  
B. R. Nechay ◽  
J. P. Saunders
Keyword(s):  
Silver Nitrate ◽  
Aqueous Suspension ◽  
Human Kidney ◽  
Silver Sulfadiazine ◽  
Constant Concentration ◽  
Inhibitory Potency ◽  
Adenosine Triphosphatases ◽  
Tissue Homogenates ◽  
Atpase Inhibition

Inhibition of adenosine triphosphatase (ATPase) by silver nitrate (AgNO3) in vitro was studied in microsomal fractions or tissue homogenates of canine brain and kidney and human kidney. In microsomal fractions, AgNO3 was an indiscriminate inhibitor of ouabain-sensitive (Na+ + K+ ATPase) and ouabain-insensitive (Mg2+ ATPase) activities, with 50% inhibition obtaining at concentrations on the order of 10–7 to 10–6 M. Changing the concentrations of Na+, K+, H+, Mg2+, and ATP did not alter the fractional inhibition of Na+ + K+ ATPase by a constant concentration of AgNO3. An aqueous suspension of silver sulfadiazine had an inhibitory potency similar to AgNO3. It was concluded that silver gives a different pattern of Na+ + K+ ATPase inhibition than other metallic inhibitors of the enzyme so far examined.

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