scholarly journals A computational study about the mechanism of action of metformin on hepatic gluconeogenesis, focused on its ability to create stable pseudo-aromatic copper complexes

2017 ◽  
Author(s):  
Fabio Rebecchi
Keyword(s):  
Virtual Screening ◽  
Copper Complex ◽  
Copper Complexes ◽  
Competitive Inhibition ◽  
Computational Study ◽  
Competitive Inhibitor ◽  
Pharmacophore Modeling ◽  
Prosthetic Group ◽  
Glycerophosphate Dehydrogenase ◽  
Wide Range

AbstractMetformin is the best therapeutic choice for treating type 2 Diabetes.Despite this, and the fact it has been prescribed worldwide for decades, its mechanism of gluconeogenesis inhibition is still unknown.In the following work a novel mechanism of inhibition is suggested: that metformin performs its action on the target enzyme not as a pure molecule but, after sequestering endogenous cellular copper, as a copper complex.This result was obtained using chemoinformatics methods including homology modeling for the creation of the target enzyme’s tridimensional virtual structure, molecular docking for both the determination of the movement of the prosthetic group inside its cavity and for the identification of the best ligand poses for the metformin copper complexes, and eventually pharmacophore modeling and virtual screening to find alternative virtual leads that could achieve similar effects.The simulations show the complex binding as a non competitive inhibitor to the large exit of the mitochondrial glycerophosphate dehydrogenase enzyme’s FAD cavity, preventing FAD movement inside the cavity and/or quinone interaction and therefore its electron transfer function.The proposed mechanism seems to be successful at explaining a wide range of existing experimental results, both regarding measurements of metformin non-competitive inhibition of GPD2 and the role of copper and pH in its action.The virtual screening outcome of at least two similarly active purchasable molecule hints to an easy way to experimentally test the proposed mechanisms.In fact, the virtual leads are very similar to the copper complex but quite different from metformin alone, and a laboratory confirmation of their activity should plausibly imply that metformin acts in synergy with copper, giving us the ability to design new antidiabetic drugs in a novel and more rational fashion, with significant savings in research costs and efforts.

THE COMPETITIVE INHIBITION OF THE CYTOPLASMICL-α-GLYCEROPHOSPHATE DEHYDROGENASE OF SKELETAL MUSCLE BYL-α-GLYCEROPHOSPHATE

1965 ◽  
Vol 43 (1) ◽  
pp. 17-24 ◽  
Author(s):  
M. C. Blanchaer
Keyword(s):  
Skeletal Muscle ◽  
Phosphate Buffer ◽  
Competitive Inhibition ◽  
Mitochondrial Respiratory Chain ◽  
Competitive Inhibitor ◽  
Test System ◽  
Dihydroxyacetone Phosphate ◽  
Rabbit Muscle ◽  
Michaelis Constant ◽  
Glycerophosphate Dehydrogenase

The inhibition by L-α-glycerophosphate of the reduction of dihydroxyacetone phosphate by crystalline rabbit muscle NAD+-linked L-α-glycerophosphate dehydrogenase has been examined. As a result of the measurement of the absorbance at 340 mμ in a photometric test system at 26° containing 0.08–2.0 mM dihydroxyacetone phosphate, 0.14 mM NADH, and 1–1.5 μg crystalline enzyme in 1.5 ml 10 mM EDTA −0.1 M phosphate buffer at pH 7-0, the apparent Michaelis constant (Km) for dihydroxyacetone phosphate was found to be 0.363 mM (± 0.025 S.E.). L-α-Giycerophosphate, but not D-α-glycerophosphate, acted as a competitive inhibitor in this system with an apparent inhibition constant (Ki) of 0.575 mM (± 0.030). Substitution of 50 mM triethanolarnine buffer for the 0.1 M phosphate buffer lowered the Kmto 0.088 mM (± 0.019) and the Kito 0.240 mM (± 0.013). To study the enzyme at lower NADH concentrations, a fluorometric system containing 20–75 μM NADH, 5–370 μM DHAP, and 0.5–2.0 μg enzyme in 1 ml 2 mM EDTA −50 mM triethanolarnine buffer, pH 7.0 at 23°, was used. The apparent Kmfor dihydroxyacetone phosphate and Kifor L-α-glycerophosphate were 0.075 μM (± 0.020) and 0.186 mM (± 0.006) respectively, at a NADH concentration of 75 μM. Lowering the NADH concentration to 20 μM further decreased the apparent Kmand Kivalues to 0.039 mM (± 0.008) and 0.056 mM (± 0.007) respectively.A consideration of the concentrations of dihydroxyacetone phosphate and L-α-glycerophosphate in muscle during contraction suggests that the competitive inhibition of cytoplasmic L-α-glycerophosphate dehydrogenase by its product, L-α-glycerophosphate, may influence the pathway of triose phosphate utilization and also the coupling, by way of the L-α-glycerophosphate cycle, of cytoplasmic NADH-generating reactions to the mitochondrial respiratory chain.

Kinetic Aspects of the Interaction of Blood Clotting Enzymes

1968 ◽  
Vol 19 (03/04) ◽  
pp. 364-367 ◽  
Author(s):  
H. C Hemker ◽  
P. W Hemker
Keyword(s):  
Enzyme Kinetics ◽  
Blood Clotting ◽  
Competitive Inhibition ◽  
Competitive Inhibitor ◽  
Kinetics Of

SummaryThe enzyme kinetics of competitive inhibition under conditions prevailing in clotting tests are developed and a method is given to measure relative amounts of a competitive inhibitor by means of the t — D plot.

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>

Inhibition kinetics for propionate degradation using propionate-enriched mixed cultures

1998 ◽  
Vol 38 (8-9) ◽  
pp. 443-451 ◽  
Author(s):  
S. H. Hyun ◽  
J. C. Young ◽  
I. S. Kim
Keyword(s):  
Phase I ◽  
Competitive Inhibition ◽  
Gas Production ◽  
Phase Iii ◽  
Utilization Rate ◽  
Inhibition Kinetics ◽  
Wide Range ◽  
Propionate Degradation ◽  
Acetate Utilization ◽  
Velocity Coefficient

To study propionate inhibition kinetics, seed cultures for the experiment were obtained from a propionate-enriched steady-state anaerobic Master Culture Reactor (MCR) operated under a semi-continuous mode for over six months. The MCR received a loading of 1.0 g propionate COD/l-day and was maintained at a temperature of 35±1°C. Tests using serum bottle reactors consisted of four phases. Phase I tests were conducted for measurement of anaerobic gas production as a screening step for a wide range of propionate concentrations. Phase II was a repeat of phase I but with more frequent sampling and detailed analysis of components in the liquid sample using gas chromatography. In phase III, different concentrations of acetate were added along with 1.0 g propionate COD/l to observe acetate inhibition of propionate degradation. Finally in phase IV, different concentrations of propionate were added along with 100 and 200 mg acetate/l to confirm the effect of mutual inhibition. Biokinetic and inhibition coefficients were obtained using models of Monod, Haldane, and Han and Levenspiel through the use of non-linear curve fitting technique. Results showed that the values of kp, maximum propionate utilization rate, and Ksp, half-velocity coefficient for propionate conversion, were 0.257 mg HPr/mg VSS-hr and 200 mg HPr/l, respectively. The values of kA, maximum acetate utilization rate, and KsA, half-velocity coefficient for acetate conversion, were 0.216 mg HAc/mg VSS-hr and 58 mg HAc/l, respectively. The results of phase III and IV tests indicated there was non-competitive inhibition when the acetate concentration in the reactor exceeded 200 mg/l.

Discovery of Novel NAMPT Inhibitors Based on Pharmacophore Modeling and Virtual Screening Techniques

2015 ◽  
Vol 17 (10) ◽  
pp. 868-878 ◽  
Author(s):  
Qianying Yi ◽  
Lu Zhou ◽  
Xin Shao ◽  
Taijin Wang ◽  
Guangkai Bao ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Pharmacophore Modeling ◽  
Screening Techniques

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.

scholarly journals Structure-Based Virtual Screening and Biological Evaluation of Peptide Inhibitors for Polo-Box Domain

Molecules ◽  
2019 ◽  
Vol 25 (1) ◽  
pp. 107 ◽  
Author(s):  
Fang Yan ◽  
Guangmei Liu ◽  
Tingting Chen ◽  
Xiaochen Fu ◽  
Miao-Miao Niu
Keyword(s):  
Cell Cycle ◽  
Virtual Screening ◽  
Fold Increase ◽  
Pharmacophore Modeling ◽  
Biological Evaluation ◽  
Peptide Inhibitors ◽  
Regulatory Proteins ◽  
Competitive Binding Assay ◽  
M Phase ◽  
Cell Cycle Regulatory Proteins

The polo-box domain of polo-like kinase 1 (PLK1-PBD) is proved to have crucial roles in cell proliferation. Designing PLK1-PBD inhibitors is challenging due to their poor cellular penetration. In this study, we applied a virtual screening workflow based on a combination of structure-based pharmacophore modeling with molecular docking screening techniques, so as to discover potent PLK1-PBD peptide inhibitors. The resulting 9 virtual screening peptides showed affinities for PLK1-PBD in a competitive binding assay. In particular, peptide 5 exhibited an approximately 100-fold increase in inhibitory activity (IC50 = 70 nM), as compared with the control poloboxtide. Moreover, cell cycle experiments indicated that peptide 5 effectively inhibited the expression of p-Cdc25C and cell cycle regulatory proteins by affecting the function of PLK1-PBD, thereby inducing mitotic arrest at the G2/M phase. Overall, peptide 5 can serve as a potent lead for further investigation as PLK1-PBD inhibitors.

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