scholarly journals Design, synthesis and evaluation of a tripodal receptor for phosphatidylinositol phosphates

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Katharina Reeh ◽  
Peter A. Summers ◽  
Ian R. Gould ◽  
Rudiger Woscholski ◽  
Ramon Vilar
Keyword(s):  
Computational Study ◽  
Binding Mode ◽  
Molecular Probes ◽  
Membrane Phospholipids ◽  
Design Synthesis ◽  
Guest Binding ◽  
Wide Range ◽  
Free Environment ◽  
Small Molecule Receptors ◽  
Phosphatidylinositol Phosphates

Abstract Phosphatidylinositol phosphates (PIPs) are membrane phospholipids that play crucial roles in a wide range of cellular processes. Their function is dictated by the number and positions of the phosphate groups in the inositol ring (with seven different PIPs being active in the cell). Therefore, there is significant interest in developing small-molecule receptors that can bind selectively to these species and in doing so affect their cellular function or be the basis for molecular probes. However, to date there are very few examples of such molecular receptors. Towards this aim, herein we report a novel tripodal molecule that acts as receptor for mono- and bis-phosphorylated PIPs in a cell free environment. To assess their affinity to PIPs we have developed a new cell free assay based on the ability of the receptor to prevent alkaline phosphatase from hydrolysing these substrates. The new receptor displays selectivity towards two out of the seven PIPs, namely PI(3)P and PI(3,4)P2. To rationalise these results, a DFT computational study was performed which corroborated the experimental results and provided insight into the host–guest binding mode.

Discovery of Antibacterial Agents Inhibiting the Energy-Coupling Factor (ECF) Transporters by Structure-Based Virtual Screening

2020 ◽  
Author(s):  
Eleonora Diamanti ◽  
Inda Setyawati ◽  
Spyridon Bousis ◽  
leticia mojas ◽  
lotteke Swier ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Antibacterial Agents ◽  
Antimicrobial Agents ◽  
Energy Coupling ◽  
Coupling Factor ◽  
Design Synthesis ◽  
Screening Design ◽  
Starting Point ◽  
Wide Range ◽  
Vitamin Uptake

Here, we report on the virtual screening, design, synthesis and structure–activity relationships (SARs) of the first class of selective, antibacterial agents against the energy-coupling factor (ECF) transporters. The ECF transporters are a family of transmembrane proteins involved in the uptake of vitamins in a wide range of bacteria. Inhibition of the activity of these proteins could reduce the viability of pathogens that depend on vitamin uptake. Because of their central role in the metabolism of bacteria and their absence in humans, ECF transporters are novel potential antimicrobial targets to tackle infection. The hit compound’s metabolic and plasma stability, the potency (20, MIC Streptococcus pneumoniae = 2 µg/mL), the absence of cytotoxicity and a lack of resistance development under the conditions tested here suggest that this scaffold may represent a promising starting point for the development of novel antimicrobial agents with an unprecedented mechanism of action.<br>

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.

Design, Synthesis, Anti-Proliferative Evaluation and Cell Cycle Analysis of Hybrid 2-Quinolones

2019 ◽  
Vol 19 (9) ◽  
pp. 1132-1140
Author(s):  
Heba A.E. Mohamed ◽  
Hossa F. Al-Shareef
Keyword(s):  
Cell Cycle ◽  
Anticancer Agents ◽  
Biological Activities ◽  
Flow Cytometric Analysis ◽  
Annexin V ◽  
Cytotoxic Activities ◽  
Significant Group ◽  
Design Synthesis ◽  
Standard Drug ◽  
Wide Range

Background: Quinolones are a significant group of nitrogen heterocyclic compounds that exist in therapeutic agents, alkaloids, and synthetic small molecules that have important biological activities. A wide range of quinolones have been used as antituberculosis, antibacterial, anti-malarial, antifungal, anticonvulsant, anticancer agents and urease inhibitors. Methods: Ethyl 3,3-disubstituted-2-cyano propionates containing hybride quinolones derivatives were synthesized by the reaction of 1-amino-7-hydroxy-4-methylquinolin-2(1H)-one and its dibromo derivative with α, β-unsaturated carbonyl in ethanol. Results: A novel series of hybrid 2-quinolone derivatives was designed and synthesized. The compounds structures were confirmed using different spectroscopic methods and elemental analysis. The cytotoxic activities of all the compounds were assessed against HepG2 cell line in comparison with doxorubicin as a standard drug. Conclusion: Most compounds revealed superior anti-proliferative activity than the standard. Compound 4b, is the most active compound (IC50 = 0.39mM) compared with doxorubicin (IC50 = 9.23mM). DNA flow cytometric analysis of compound 4b showed cell cycle arrest at G2/M phase with a concomitant increase of cells in apoptotic phase. Dual annexin-V/ propidium iodide staining assay of compound 4b revealed that the selected candidate increased the apoptosis of HepG-2 cells more than control.

Design, synthesis, anti-cancer evaluation and binding mode studies of benzimidazole/benzoxazole linked β-carboline derivatives

2021 ◽  
Vol 1226 ◽  
pp. 129351
Author(s):  
Reddymasu Sireesha ◽  
Reddymasu Sreenivasulu ◽  
Choragudi Chandrasekhar ◽  
Surender Singh Jadav ◽  
Y. Pavani ◽  
...  
Keyword(s):  
Binding Mode ◽  
Design Synthesis ◽  
Anti Cancer

Computational study of the binding mode, action mechanism and potency of pregabalin through molecular docking and quantum mechanical descriptors

2021 ◽  
Vol 1199 ◽  
pp. 113200
Author(s):  
Lorena Meneses ◽  
Sebastian Cuesta Hoyos ◽  
Guillermo Salgado Morán ◽  
Patricio Muñoz C. ◽  
Lorena Gerli Candia ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Computational Study ◽  
Binding Mode ◽  
Quantum Mechanical ◽  
Action Mechanism

scholarly journals Design, Synthesis, and Evaluation of Coumarin-Based Molecular Probes for Imaging of Myelination

2011 ◽  
Vol 54 (7) ◽  
pp. 2331-2340 ◽  
Author(s):  
Changning Wang ◽  
Chunying Wu ◽  
Junqing Zhu ◽  
Robert H. Miller ◽  
Yanming Wang
Keyword(s):  
Molecular Probes ◽  
Design Synthesis

scholarly journals A Computational Study on the Role of Parameters for Identification of Thyroid Nodules by Infrared Images (and Comparison with Real Data)

Sensors ◽  
2021 ◽  
Vol 21 (13) ◽  
pp. 4459
Author(s):  
José R. González ◽  
Charbel Damião ◽  
Maira Moran ◽  
Cristina A. Pantaleão ◽  
Rubens A. Cruz ◽  
...  
Keyword(s):  
Heat Transfer ◽  
Thyroid Nodules ◽  
Numerical Study ◽  
Computational Study ◽  
Internal Heat ◽  
Heat Transfer Process ◽  
The Body ◽  
Physical Parameters ◽  
Infrared Sensors ◽  
Wide Range

According to experts and medical literature, healthy thyroids and thyroids containing benign nodules tend to be less inflamed and less active than those with malignant nodules. It seems to be a consensus that malignant nodules have more blood veins and more blood circulation. This may be related to the maintenance of the nodule’s heat at a higher level compared with neighboring tissues. If the internal heat modifies the skin radiation, then it could be detected by infrared sensors. The goal of this work is the investigation of the factors that allow this detection, and the possible relation with any pattern referent to nodule malignancy. We aim to consider a wide range of factors, so a great number of numerical simulations of the heat transfer in the region under analysis, based on the Finite Element method, are performed to study the influence of each nodule and patient characteristics on the infrared sensor acquisition. To do so, the protocol for infrared thyroid examination used in our university’s hospital is simulated in the numerical study. This protocol presents two phases. In the first one, the body under observation is in steady state. In the second one, it is submitted to thermal stress (transient state). Both are simulated in order to verify if it is possible (by infrared sensors) to identify different behavior referent to malignant nodules. Moreover, when the simulation indicates possible important aspects, patients with and without similar characteristics are examined to confirm such influences. The results show that the tissues between skin and thyroid, as well as the nodule size, have an influence on superficial temperatures. Other thermal parameters of thyroid nodules show little influence on surface infrared emissions, for instance, those related to the vascularization of the nodule. All details of the physical parameters used in the simulations, characteristics of the real nodules and thermal examinations are publicly available, allowing these simulations to be compared with other types of heat transfer solutions and infrared examination protocols. Among the main contributions of this work, we highlight the simulation of the possible range of parameters, and definition of the simulation approach for mapping the used infrared protocol, promoting the investigation of a possible relation between the heat transfer process and the data obtained by infrared acquisitions.

Design, Synthesis and Docking Studies of Thioimidazolyl Diketoacid Derivatives Targeting HIV-1 Integrase

2021 ◽  
Vol 17 ◽  
Author(s):  
Nafiseh Karimi ◽  
Rouhollah Vahabpour Roudsari ◽  
Zahra Hajimahdi ◽  
Afshin Zarghi
Keyword(s):  
Drug Target ◽  
Enzyme Assay ◽  
Binding Mode ◽  
Docking Studies ◽  
Integrase Inhibitors ◽  
Design Synthesis ◽  
Ic50 Values ◽  
Novel Structures ◽  
Anti Hiv ◽  
Hiv 1

Background: Integrase enzyme is a validated drug target to discover novel structures as anti-HIV-1 agents. Objective: Novel series of thioimidazolyl diketo acid derivatives characterizing various substituents at N-1 and 2-thio positions of central ring were developed as HIV-1 integrase inhibitors. Results: The obtained molecules were evaluated in the enzyme assay, displaying promising integrase inhibitory activity with IC50 values ranging from 0.9 to 7.7 M. The synthesized compounds were also tested for antiviral activity and cytotoxicity using HeLa cells infected by the single-cycle replicable HIV-1 NL4-3. Conclusion: The most potent compound was 18i with EC50=19 µM, IC50 0.9 µM and SI= 10.5. Docking studies indicated that the binding mode of the active molecule is well aligned with the known HIV-1 integrase inhibitors.

scholarly journals Structural and functional studies of pyruvate carboxylase regulation by cyclic di-AMP in lactic acid bacteria

2017 ◽  
Vol 114 (35) ◽  
pp. E7226-E7235 ◽  
Author(s):  
Philip H. Choi ◽  
Thu Minh Ngoc Vu ◽  
Huong Thi Pham ◽  
Joshua J. Woodward ◽  
Mark S. Turner ◽  
...  
Keyword(s):  
Binding Site ◽  
Conformational Changes ◽  
Pyruvate Carboxylase ◽  
Adenosine Monophosphate ◽  
Binding Mode ◽  
Functional Studies ◽  
Cellular Processes ◽  
Wide Range ◽  
A Site ◽  
Amp Inhibition

Cyclic di-3′,5′-adenosine monophosphate (c-di-AMP) is a broadly conserved bacterial second messenger that has been implicated in a wide range of cellular processes. Our earlier studies showed that c-di-AMP regulates central metabolism inListeria monocytogenesby inhibiting its pyruvate carboxylase (LmPC), a biotin-dependent enzyme with biotin carboxylase (BC) and carboxyltransferase (CT) activities. We report here structural, biochemical, and functional studies on the inhibition ofLactococcus lactisPC (LlPC) by c-di-AMP. The compound is bound at the dimer interface of the CT domain, at a site equivalent to that in LmPC, although it has a distinct binding mode in the LlPC complex. This binding site is not well conserved among PCs, and only a subset of these bacterial enzymes are sensitive to c-di-AMP. Conformational changes in the CT dimer induced by c-di-AMP binding may be the molecular mechanism for its inhibitory activity. Mutations of residues in the binding site can abolish c-di-AMP inhibition. InL. lactis, LlPC is required for efficient milk acidification through its essential role in aspartate biosynthesis. The aspartate pool inL. lactisis negatively regulated by c-di-AMP, and high aspartate levels can be restored by expression of a c-di-AMP–insensitive LlPC. LlPC has high intrinsic catalytic activity and is not sensitive to acetyl-CoA activation, in contrast to other PC enzymes.

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