Computationally motivated synthesis and enzyme kinetic evaluation of N-(β-d-glucopyranosyl)-1,2,4-triazolecarboxamides as glycogen phosphorylase inhibitors

Following our recent study of N-(β-D-glucopyranosyl)-oxadiazole-carboxamides (Polyák et al., Biorg. Med. Chem. 2013, 21, 5738) revealed as moderate inhibitors of glycogen phosphorylase (GP), in silico docking calculations using Glide have been performed on N-(β-D-glucopyranosyl)-1,2,4-triazolecarboxamides with different aryl substituents predicting more favorable binding at GP. The ligands were subsequently synthesized in moderate yields using N-(2,3,4,6-terta-O-acetyl-β-D-glucopyranosyl)-tetrazole-5-carboxamide as starting material. Kinetics experiments against rabbit muscle glycogen phosphorylase b (RMGPb) revealed the ligands to be low µM GP inhibitors; the phenyl analogue (Ki = 1 µM) is one of the most potent N-(β-D-glucopyranosyl)-heteroaryl-carboxamide-type inhibitors of the GP catalytic site discovered to date. Based on QM and QM/MM calculations, the potency of the ligands is predicted to arise from favorable intra- and intermolecular hydrogen bonds formed by the most stable solution phase tautomeric (t2) state of the 1,2,4-triazole in a conformationally dynamic system. ADMET property predictions revealed the compounds to have promising pharmacokinetic properties without any toxicity. This study highlights the benefits of a computationally lead approach to GP inhibitor design

Practically Impractical: Contemplative Practices in Science

Contemplation has been described as a “long, loving look at the real,” a characterization that could equally well apply to science. In this paper, I frame a contemplative approach to the teaching and practice of science which draws strongly on the Christian monastic traditions. Students, in particular, struggle with the ever increasing information density in their course work which can cloud their understanding of the relationship of their work to broader contexts. I suggest that the monastic counsels of intentional simplicity, deep listening and constancy can provide a foundation for the design of science courses which help students engage more deeply with their work in the midst of a deluge of information, particularly visual and graphical information. I present four different contemplative practices suited for use in the scientific classroom and research lab: a simple, discreet stilling exercise for focus and attention, a ‘beholding’ approach to exploring visual data and two writing exercises designed for laboratory researchers

The Effective Fragment Molecular Orbital Method for Fragments Connected by Covalent Bonds

We extend the effective fragment molecular orbital method (EFMO) into treating fragments connected by covalent bonds. The accuracy of EFMO is compared to FMO and conventional ab initio electronic structure methods for polypeptides including proteins. Errors in energy for RHF and MP2 are within 2 kcal/mol for neutral polypeptides and 6 kcal/mol for charged polypeptides similar to FMO but obtained two to five times faster. For proteins, the errors are also within a few kcal/mol of the FMO results. We developed both the RHF and MP2 gradient for EFMO. Compared to ab initio, the EFMO optimized structures had an RMSD of 0.40 and 0.44 {\AA} for RHF and MP2, respectively.Comment: Revised manuscrip

Organic Dye Design Tools for Efficient Photocurrent Generation in Dye‐Sensitized Solar Cells: Exciton Binding Energy and Electron Acceptors

The relationship between the exciton binding energies of several pure organic dyes and their chemical structures is explored using density functional theory calculations in order to optimize the molecular design in terms of the light‐to‐electric energy‐conversion efficiency in dye‐sensitized solar cell devices. Comparing calculations with measurements reveals that the exciton binding energy and quantum yield are inversely correlated, implying that dyes with lower exciton binding energy produce electric current from the absorbed photons more efficiently. When a strong electron‐accepting moiety is inserted in the middle of the dye framework, the light‐to‐electric energy‐conversion behavior significantly deteriorates. As verified by electronic‐structure calculations, this is likely due to electron localization near the electron‐deficient group. The combined computational and experimental design approach provides insight into the functioning of organic photosensitizing dyes for solar‐cell applications. This is exemplified by the development of a novel, all‐organic dye (EB‐01) exhibiting a power conversion efficiency of over 9%. A combined computational and experimental design approach provides insight into the functioning of organic photosensitizer dyes for solar cell applications. Comparing calculations with measurements reveals that the exciton binding energy and quantum yield are inversely correlated. When a strong electron‐accepting moiety is inserted in the middle of the dye framework, the light‐to‐electric energy conversion behavior significantly deteriorates.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91137/1/adfm_201101961_sm_suppl.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/91137/2/1606_ftp.pd

A QM/MM study of the nature of the entatic state in plastocyanin

Plastocyanin is a copper containing protein that is involved in the electron transfer process in photosynthetic organisms. The active site of plastocyanin is described as an entatic state whereby its structure represents a compromise between the structures favored by the oxidized and reduced forms. In this study, the nature of the entatic state is investigated through density functional theory-based hybrid quantum mechanics/molecular mechanics (QM/MM) molecular dynamics simulations. The strain energy is computed to be 12.8 kcal/mol and 14.5 kcal/mol for the oxidized and reduced forms of the protein, indicating that the active site has an intermediate structure. It is shown that the energy gap between the oxidized and reduced forms varies significantly with the fluctuations in the structure of the active site at room temperature. An accurate determination of the reorganization energy requires averaging over conformation and a large region of the protein around the active site to be treated at the quantum mechanical level

Grading And Assessments: Correlations Of Variables Affecting Teaching And Course Assessments

Faculty assessments are a hot topic in academia. Mostly considered an unproven statistic holding the professor hostage for a good grade, the benefits are still in discussion.  At course end, we expect students to have the ability to analyze what we think they should have learned.  In reality, most students do not have the maturity to realize correlation for what you put into your education is what you get out.  Consensus is that it does not happen the way we plan.  Adding to the assessment issue is the clear fact that today most universities are adjunct professor-driven. Given these facts, the authors have statistically studied teaching assessments and associated grade point averages (GPA) representing academic rigor at a major non-profit university over the past three years.  The authors’ hypothesis is that there is no correlation between the two statistics.  This paper reviews the literature, provides the study methodology, and presents the findings

Cadherin2 (N-cadherin) plays an essential role in zebrafish cardiovascular development

BACKGROUND: Cadherins are cell surface adhesion molecules that play important roles in development of vertebrate tissues and organs. We studied cadherin2 expression in developing zebrafish heart using in situ hybridization and immunocytochemical methods, and we found that cadherin2 was strongly expressed by the myocardium of the embryonic zebrafish. To gain insight into cadherin2 role in the formation and function of the heart, we analyzed cardiac differentiation and performance in a cadherin2 mutant, glass onion (glo). RESULTS: We found that the cadherin2 mutant had enlarged pericardial cavity, disorganized atrium and ventricle, and reduced expression of a ventricular specific marker vmhc. Individual myocardiocytes in the glo mutant embryos became round shaped and loosely aggregated. In vivo measurements of cardiac performance revealed that the mutant heart had significantly reduced heart rate, stroke volume and cardiac output compared to control embryos. Formation of the embryonic vascular system in the glo mutants was also affected. CONCLUSION: Our results suggest that cadherin2 plays an essential role in zebrafish cardiovascular development. Although the exact mechanisms remain unknown as to the formation of the enlarged pericardium and reduced peripheral blood flow, it is clear that myocardiocyte differentiation and physiological cardiovascular performance is impaired when cadherin2 function is disrupted