Mapping the ribonucleolytic active site of bovine seminal ribonuclease. The binding of pyrimidinyl phosphonucleotide inhibitors

Dossi, Kyriaki; Tsirkone, V.G.; Hayes, Joseph M.; Matoušek, J.; Poučková, P; Souček, J; Zadinová, M; Zographos, S.E.; Leonidas, D.D.

doi:10.1016/j.ejmech.2009.06.039

Cited by 8 publications

(4 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It consists of a two‐step reaction starting with a transphosphorylation of the nucleic acid strand to produce an 2’,3’‐cyclic phosphodiester intermediate which is then hydrolyzed to release a 3’‐nucleotide. It was thereafter established that both enzymes, BS‐RNase and RNase A, share the same active site . Two histidines, His‐12 and His‐119, are directly involved in the reaction and a lysine, Lys‐41, stabilizes the transition state .…”

Section: Resultsmentioning

confidence: 99%

Stability strengths and weaknesses in protein structures detected by statistical potentials: Application to bovine seminal ribonuclease

2015

View full text Add to dashboard Cite

We present an in silico method to estimate the contribution of each residue in a protein to its overall stability using three database-derived statistical potentials that are based on inter-residue distances, backbone torsion angles and solvent accessibility, respectively. Residues that contribute very unfavorably to the folding free energy are defined as stability weaknesses, whereas residues that show a highly stabilizing contribution are called stability strengths. Strengths and/or weaknesses on residues that are in spatial contact are clustered into 3-dimensional (3D) stability patches. The identification and analysis of strength- and weakness-containing regions in a protein may reveal structural or functional characteristics, and/or interesting spots to introduce mutations. To illustrate the power of our method, we apply it to bovine seminal ribonuclease. This enzyme catalyzes the degradation of RNA strands, and has the peculiarity of undergoing 3D domain swapping in physiological conditions. The weaknesses and strengths were compared among the monomeric, dimeric and swapped dimeric forms. We identified weaknesses among the catalytic residues and a mixture of weaknesses and strengths among the substrate-binding residues in the three forms. In the regions involved in 3D swapping, we observed an accumulation of weaknesses in the monomer, which disappear in the dimer and especially in the swapped dimer. Moreover, monomeric homologous proteins were found to exhibit less weaknesses in these regions, whereas mutants known to favor unswapped dimerization appear stabilized in this form. Our method has several perspectives for functional annotation, rational prediction of targeted mutations, and mapping of stability changes upon conformational rearrangements.

show abstract

Section: Resultsmentioning

confidence: 99%

Stability strengths and weaknesses in protein structures detected by statistical potentials: Application to bovine seminal ribonuclease

2015

View full text Add to dashboard Cite

show abstract

“…Theoretical studies indicate that all six phytochemicals have good oral bioavailability, − so they could be good drug candidates. Other than chlorogenic acid, the other five hydroxycinnamic acid derivatives may absorb through passive diffusion, which might be because of their size.…”

Section: Discussionmentioning

confidence: 99%

“…QikProp (Schrödinger Inc., Portland, OR) was used for calculating the ADME and drug-like properties of these compounds. These descriptors are QPlogBB (predicted brain/blood partition coefficient), percent human-oral absorption (predicted human oral absorption on 0–100% scale, based on a quantitative multiple linear regression model), QPlogS (predicted aqueous solubility), number of violations of Lipinski’s rule of five (the rule is “molecular weight < 500, QPlogPo/w (predicted octanol/water partition coefficient) < 5, hydrogen bond donor ≤ 5, hydrogen bond acceptor ≤ 10”), and number of violations of Jorgensen’s rule of three (the rule is “QPlogS > −5.7, QPPCaco (predicted apparent Caco-2 cell permeability) > 22 nm/s, number of primary metabolites < 7”). , The recommended range for QPlogBB is from −3.0 to 1.2, that for percent human-oral absorption is 25–80%, that for QPlogS is from −6.5 to 0.5, and permitted violation of the rules of five and three are 1 and 0, respectively. These descriptors described the ADME, drug-like properties, and oral bioavailability of the compounds.…”

Section: Methodsmentioning

confidence: 99%

Interaction of Cinnamic Acid Derivatives with Commercial Hypoglycemic Drugs on 2-Deoxyglucose Uptake in 3T3-L1 Adipocytes

Prabhakar

Doble

2011

J. Agric. Food Chem.

View full text Add to dashboard Cite

Hydroxycinnamic acid derivatives are naturally occurring substances found in fruits, vegetables, and flowers and are consumed as dietary phenolic compounds. The effect of cinnamic acid, ferulic acid, p-coumaric acid, eugenol, chlorogenic acid, and caffeic acid, alone and in combination with two commercial oral hypoglycemic drugs (OHD), namely, thiazolidinedione (THZ) and metformin, on the uptake of 2-deoxyglucose (2DG) by 3T3-L1 adipocytes is studied. All of the phytochemicals other than cinnamic acid show synergistic interaction in 2DG uptake with both of the OHDs. THZ (20 μM) in combination with ferulic acid (25 μM) or p-coumaric acid (25 μM) increases 2DG uptake by 7- or 6.34-fold, respectively, with respect to control, whereas metformin (20 μM), along with ferulic acid (25 μM) or cinnamic acid (25 μM), increases 2DG uptake by 6.45- or 5.87-fold, respectively, when compared to control. Chlorogenic and cinnamic acids increased the expression of PPARγ, whereas other hydroxycinnamic acids enhanced the expression of PI3K, indicating different mechanisms of action between these compounds. These phytochemicals were able to reduce the expressions of the fatty acid synthase and HMG CoA reductase genes, indicating that they may be able to reduce the secondary complications caused by the accumulation of lipids. These studies suggest that hydroxycinnamic acid derivatives may be beneficial for the treatment of diabetes mellitus. They may act as a supplement with commercial drugs and may reduce the secondary complications caused by OHDs.

show abstract

“…QikProp Õ (Schrödinger Inc., Portland, USA) software was used for calculating the ADME and the drug-likeness properties of these compounds. The descriptors for these properties are QPlogBB (predicted brain/blood partition coefficient), percent human oral absorption (predicted human oral absorption on a 0100% scale, based on a quantitative multiple linear regression model), QPlogS (predicted aqueous solubility), number of violations of Lipinski's rule of five (the rule is: molecular weight <500, log o/w partition coefficient <5, number of hydrogen bond donor 5, number of hydrogen bond acceptor 10) and number of violations of Jorgensen's rule of three (the rule is: predicted aqueous solubility (QPlogS)> À5.7, predicted apparent Caco-2 cell permeability >22 nm/s, number of primary metabolites <7) [Dossi et al 2009;Duchowicz et al 2007]. The recommended ranges are: bloodbrain partition coefficient À3.0 to 1.2, percent human oral absorption 25 to 80%, QPlogS À6.5 to 0.5, and the permitted violations of the rule of five and rule of three are 1 and 0, respectively.…”

Section: Calculation Of Absorption Distribution Metabolism and Excrmentioning

confidence: 99%

Effect of natural products on commercial oral antidiabetic drugs in enhancing 2-deoxyglucose uptake by 3T3-L1 adipocytes

Prabhakar

Doble

2011

Therapeutic Advances in Endocrinology

View full text Add to dashboard Cite

Abstract:Objective: The management of diabetes with insulin and synthetic oral hypoglycemic drugs (OHDs) can produce serious side effects and in addition fails to prevent diabetes-related complications in many patients. A new diabetes management strategy is needed that is more effective and has fewer side effects. Methods: This paper analyzes the dose-and time-dependent effect of three phytochemicals: berberine, arecoline and vanillic acid, and two antidiabetic drugs: 2,4-thiazolidinedione (TZD) and metformin, on the uptake of 2-deoxyglucose (2DG) by 3T3-L1 adipocytes. The interactions of the phytochemicals with the OHDs were analyzed with isobolograms and the combination index.Results: TZD and berberine increased 2DG uptake by 3.3-fold (with respect to control) at 15 mM and 25 mM, respectively. The same concentrations of arecoline and vanillic acid increased 2DG uptake by 3.2-and 2.9-fold, respectively, when compared with the basal level. Berberine and arecoline acted synergistically with both the OHDs, whereas vanillic acid had an additive interaction with TZD and an antagonistic interaction with metformin. Arecoline significantly increased the translocation of GLUT4 via the PPARg pathway, whereas berberine and vanillic acid did this via the AMPK-dependent pathway. Conclusions: These phytochemicals significantly reduced the expression of the enzymes involved in fatty acid and cholesterol synthesis, indicating that they might help prevent the secondary complications of diabetes. The current study suggests that berberine and arecoline could allow dosage reduction of OHDs, which could also lead to a reduction in the toxicity and side effects caused by OHDs.Keywords: berberine, 2-deoxyglucose, isobologram, synergy, vanillic acid Introduction Diabetes mellitus (DM) is a chronic endocrine metabolic disorder characterized by hyperglycemia. It is caused by inadequate insulin, either in its production or its function [Harris and Zimmet, 1997]. The disorder can be classified into type 1 (insulin-dependent DM) and type 2 (noninsulin-dependent DM). The latter accounts for more than 90% of all diabetes cases and is caused mainly by peripheral insulin resistance and impaired insulin secretion. It is often associated with lipid and lipoprotein disorders [Ciresi et al. 2007;Oh et al. 2005]. The metabolic disorder includes alterations in carbohydrates, lipids and protein metabolism.

show abstract

Mapping the ribonucleolytic active site of bovine seminal ribonuclease. The binding of pyrimidinyl phosphonucleotide inhibitors

Cited by 8 publications

References 78 publications

Stability strengths and weaknesses in protein structures detected by statistical potentials: Application to bovine seminal ribonuclease

Stability strengths and weaknesses in protein structures detected by statistical potentials: Application to bovine seminal ribonuclease

Interaction of Cinnamic Acid Derivatives with Commercial Hypoglycemic Drugs on 2-Deoxyglucose Uptake in 3T3-L1 Adipocytes

Effect of natural products on commercial oral antidiabetic drugs in enhancing 2-deoxyglucose uptake by 3T3-L1 adipocytes

Contact Info

Product

Resources

About