Computational Chemistry and Biology Group

Montevideo, Uruguay

Computational Chemistry and Biology Group

Montevideo, Uruguay
SEARCH FILTERS
Time filter
Source Type

Elmabsout A.A.,Örebro University | Kumawat A.,Örebro University | Saenz-Mendez P.,Computational Chemistry and Biology Group | Krivospitskaya O.,Örebro University | And 8 more authors.
PLoS ONE | Year: 2012

Background: All-trans retinoic acid (atRA) plays an essential role in the regulation of gene expression, cell growth and differentiation and is also important for normal cardiovascular development but may in turn be involved in cardiovascular diseases, i.e. atherosclerosis and restenosis. The cellular atRA levels are under strict control involving several cytochromes P450 isoforms (CYPs). CYP26 may be the most important regulator of atRA catabolism in vascular cells. The present study describes the molecular cloning, characterization and function of atRA-induced expression of a spliced variant of the CYP26B1 gene. Methodology/Principal Findings: The coding region of the spliced CYP26B1 lacking exon 2 was amplified from cDNA synthesized from atRA-treated human aortic smooth muscle cells and sequenced. Both the spliced variant and full length CYP26B1 was found to be expressed in cultured human endothelial and smooth muscle cells, and in normal and atherosclerotic vessel. atRA induced both variants of CYP26B1 in cultured vascular cells. Furthermore, the levels of spliced mRNA transcript were 4.5 times higher in the atherosclerotic lesion compared to normal arteries and the expression in the lesions was increased 20-fold upon atRA treatment. The spliced CYP26B1 still has the capability to degrade atRA, but at an initial rate one-third that of the corresponding full length enzyme. Transfection of COS-1 and THP-1 cells with the CYP26B1 spliced variant indicated either an increase or a decrease in the catabolism of atRA, probably depending on the expression of other atRA catabolizing enzymes in the cells. Conclusions/Significance: Vascular cells express the spliced variant of CYP26B1 lacking exon 2 and it is also increased in atherosclerotic lesions. The spliced variant displays a slower and reduced degradation of atRA as compared to the full-length enzyme. Further studies are needed, however, to clarify the substrate specificity and role of the CYP26B1 splice variant in health and disease. © 2012 Elmabsout et al.


A new homology model of human microsomal epoxide hydrolase (mEH) was derived based on multiple templates. The model obtained was fully evaluated, including MD simulations and ensemble-based docking, showing that the quality of the structure is better than that of only previously known model. Particularly, a catalytic triad was clearly identified, in agreement with the experimental information available. Analysis of intermediates in the enzymatic mechanism led to the identification of key residues for substrate binding, stereoselectivity and intermediate stabilization during the reaction. In particular, we have confirmed the role of the oxyanion hole and the conserved motif (HGXP) in epoxide hydrolases; in excellent agreement with known experimental and computational data on similar systems. The model obtained is the first one that fully agrees with all the experimental observations on the system. This article is protected by copyright. All rights reserved.


Awadalla M.K.A.,Hail University | Alshammari T.M.,Hail University | Eriksson L.A.,Gothenburg University | Saenz-Mendez P.,Computational Chemistry and Biology Group
Molecules | Year: 2016

A new CYP26A1 homology model was built based on the crystal structure of cyanobacterial CYP120A1. The model quality was examined for stereochemical accuracy, folding reliability, and absolute quality using a variety of different bioinformatics tools. Furthermore, the docking capabilities of the model were assessed by docking of the natural substrate all-trans-retinoic acid (atRA), and a group of known azole- and tetralone-based CYP26A1 inhibitors. The preferred binding pose of atRA suggests the (4S)-OH-atRA metabolite production, in agreement with recently available experimental data. The distances between the ligands and the heme group iron of the enzyme are in agreement with corresponding distances obtained for substrates and azole inhibitors for other cytochrome systems. The calculated theoretical binding energies agree with recently reported experimental data and show that the model is capable of discriminating between natural substrate, strong inhibitors (R116010 and R115866), and weak inhibitors (liarozole, fluconazole, tetralone derivatives). © 2016 by the authors; licensee MDPI, Basel, Switzerland.


Saenz-Mendez P.,Computational Chemistry and Biology Group | Elmabsout A.A.,Örebro University | Savenstrand H.,Örebro University | Awadalla M.K.A.,Örebro University | And 3 more authors.
Journal of Chemical Information and Modeling | Year: 2012

Homology models of CYP26B1 (cytochrome P450RAI2) and CYP26B1 spliced variant were derived using the crystal structure of cyanobacterial CYP120A1 as template for the model building. The quality of the homology models generated were carefully evaluated, and the natural substrate all-trans-retinoic acid (atRA), several tetralone-derived retinoic acid metabolizing blocking agents (RAMBAs), and a well-known potent inhibitor of CYP26B1 (R115866) were docked into the homology model of full-length cytochrome P450 26B1. The results show that in the model of the full-length CYP26B1, the protein is capable of distinguishing between the natural substrate (atRA), R115866, and the tetralone derivatives. The spliced variant of CYP26B1 model displays a reduced affinity for atRA compared to the full-length enzyme, in accordance with recently described experimental information. © 2012 American Chemical Society.


Bermudez E.,Computational Chemistry and Biology Group | Ventura O.N.,Computational Chemistry and Biology Group | Eriksson L.A.,Gothenburg University | Saenz-Mendez P.,Computational Chemistry and Biology Group
Computational Biology and Chemistry | Year: 2014

A new homology model of cyclohexanone monooxygenase (CHMO) from Acinetobacter calcoaceticus is derived based on multiple templates, and in particular the crystal structure of CHMO from Rhodococcus sp. The derived model was fully evaluated, showing that the quality of the new structure was improved over previous models. Critically, the nicotinamide cofactor is included in the model for the first time. Analysis of several molecular dynamics snapshots of intermediates in the enzymatic mechanism led to a description of key residues for cofactor binding and intermediate stabilization during the reaction, in particular Arg327 and the well known conserved motif (FxGxxxHxxxW) in Baeyer-Villiger monooxygenases, in excellent agreement with known experimental and computational data. © 2014 Elsevier Ltd.


Fagan V.,National University of Ireland | Bonham S.,National University of Ireland | Carty M.P.,National University of Ireland | Saenz-Mendez P.,Computational Chemistry and Biology Group | And 2 more authors.
Bioorganic and Medicinal Chemistry | Year: 2012

Synthesis and cytotoxicity of imidazo[5,4-f]benzimidazolequinones and iminoquinone derivatives is described, enabling structure-activity relationships to be obtained. The most promising compound (an iminoquinone derivative) has undergone National Cancer Institute (NCI) 60 cell line (single and five dose) screening, and using the NCI COMPARE program, has shown correlation to NQO1 activity and to other NQO1 substrates. Common structural features suggest that the iminoquinone moiety is significant with regard to NQO1 specificity. Computational docking into the active site of NQO1 was performed, and the first comprehensive mitomycin C (MMC)-NQO1 docking study is presented. Small distances for hydride reduction and high binding affinities are characteristic of MMC and of iminoquinones showing correlations with NQO1 via COMPARE analysis. Docking also indicated that the presence of a substituent capable of hydrogen bonding to the His194 residue is important in influencing the orientation of the substrate in the NQO1 active site, leading to more efficient reduction. © 2012 Elsevier Ltd. All rights reserved.


Ventura O.N.,Computational Chemistry and Biology Group | Saenz-Mendez P.,Computational Chemistry and Biology Group | Saenz-Mendez P.,Physical Organic Chemistry and Bioprocesses Group | Bottinelli F.,Computational Chemistry and Biology Group
Theoretical Chemistry Accounts | Year: 2011

Density functional and MP2 calculations with extended basis sets were performed on the species participating in both the previously suggested and a newly proposed mechanisms of partial dechlorination of chloropicrin by simple sulfur species, both in gas phase and in a simulated water environment. Thermochemistry of both mechanisms in the gas phase was also studied using the chemical models G3 and G4. It is shown that the previously proposed reductive dehalogenation is not thermodynamically feasible at room temperature, as it should be according to the experimental evidence. Although inclusion of the solvent improves the results with respect to gas phase, the thermodynamics of the proposed mechanism by Zheng et al. is still unfavorable for obtaining the experimental products. An alternative mechanism is then proposed, involving the formation of HSCl, which is the intermediate that then undergoes redox reactions. Such a mechanism is exothermic and spontaneous, according to the computational results, and produces elementary sulfur in agreement with the experimental facts. © 2011 Springer-Verlag.


PubMed | Hail University, Computational Chemistry and Biology Group and Gothenburg University
Type: Journal Article | Journal: Molecules (Basel, Switzerland) | Year: 2016

A new CYP26A1 homology model was built based on the crystal structure of cyanobacterial CYP120A1. The model quality was examined for stereochemical accuracy, folding reliability, and absolute quality using a variety of different bioinformatics tools. Furthermore, the docking capabilities of the model were assessed by docking of the natural substrate all-trans-retinoic acid (atRA), and a group of known azole- and tetralone-based CYP26A1 inhibitors. The preferred binding pose of atRA suggests the (4S)-OH-atRA metabolite production, in agreement with recently available experimental data. The distances between the ligands and the heme group iron of the enzyme are in agreement with corresponding distances obtained for substrates and azole inhibitors for other cytochrome systems. The calculated theoretical binding energies agree with recently reported experimental data and show that the model is capable of discriminating between natural substrate, strong inhibitors (R116010 and R115866), and weak inhibitors (liarozole, fluconazole, tetralone derivatives).


PubMed | Computational Chemistry and Biology Group and Gothenburg University
Type: | Journal: Computational biology and chemistry | Year: 2014

A new homology model of cyclohexanone monooxygenase (CHMO) from Acinetobacter calcoaceticus is derived based on multiple templates, and in particular the crystal structure of CHMO from Rhodococcus sp. The derived model was fully evaluated, showing that the quality of the new structure was improved over previous models. Critically, the nicotinamide cofactor is included in the model for the first time. Analysis of several molecular dynamics snapshots of intermediates in the enzymatic mechanism led to a description of key residues for cofactor binding and intermediate stabilization during the reaction, in particular Arg327 and the well known conserved motif (FxGxxxHxxxW) in Baeyer-Villiger monooxygenases, in excellent agreement with known experimental and computational data.


PubMed | Computational Chemistry and Biology Group
Type: Journal Article | Journal: Journal of chemical information and modeling | Year: 2012

Homology models of CYP26B1 (cytochrome P450RAI2) and CYP26B1 spliced variant were derived using the crystal structure of cyanobacterial CYP120A1 as template for the model building. The quality of the homology models generated were carefully evaluated, and the natural substrate all-trans-retinoic acid (atRA), several tetralone-derived retinoic acid metabolizing blocking agents (RAMBAs), and a well-known potent inhibitor of CYP26B1 (R115866) were docked into the homology model of full-length cytochrome P450 26B1. The results show that in the model of the full-length CYP26B1, the protein is capable of distinguishing between the natural substrate (atRA), R115866, and the tetralone derivatives. The spliced variant of CYP26B1 model displays a reduced affinity for atRA compared to the full-length enzyme, in accordance with recently described experimental information.

Loading Computational Chemistry and Biology Group collaborators
Loading Computational Chemistry and Biology Group collaborators