Effect of peptide-based captopril analogues on angiotensin converting enzyme activity and peroxynitrite-mediated tyrosine nitration

Angiotensin converting enzyme (ACE) regulates the blood pressure by converting angiotensin I to angiotensin II and bradykinin to bradykinin 1-7. These two reactions elevate the blood pressure as angiotensin II and bradykinin are vasoconstrictory and vasodilatory hormones, respectively. Therefore, inhibition of ACE is an important strategy for the treatment of hypertension. The natural substrates of ACE, i.e., angiotensin II and bradykinin, contain a Pro-Phe motif near the site of hydrolysis. Therefore, there may be a Pro-Phe binding pocket at the active site of ACE, which may facilitate the substrate binding. In view of this, we have synthesized a series of thiol-and selenol-containing dipeptides and captopril analogues and studied their ACE inhibition activities. This study reveals that both the selenol or thiol moiety and proline residues are essential for ACE inhibition. Although the introduction of a Phe residue to captopril and its selenium analogue considerably reduces the inhibitory effect, there appears to be a Phe binding pocket at the active site of ACE.

Synthesis and applications of propargyl pentafluorophenyl carbonate for peptide synthesis

Propargyl pentafluorophenyl carbonate was synthesised in quantitative yield by the reaction of propargyl chloroformate and pentafluorophenol. All the N-propargyloxycarbonyl (N-Poc) amino acids were obtained in good yield. The use of Poc-OPfp in peptide synthesis has been explored. (C) 2002 Elsevier Science Ltd. All rights reserved.

Special Issue: Engineering applications of representations of function, Part 1

In engineering design, the end goal is the creation of an artifact, product, system, or process that fulfills some functional requirements at some desired level of performance. As such, knowledge of functionality is essential in a wide variety of tasks in engineering activities, including modeling, generation, modification, visualization, explanation, evaluation, diagnosis, and repair of these artifacts and processes. A formal representation of functionality is essential for supporting any of these activities on computers. The goal of Parts 1 and 2 of this Special Issue is to bring together the state of knowledge of representing functionality in engineering applications from both the engineering and the artificial intelligence (AI) research communities.

Antioxidant activity of peptide-based angiotensin converting enzyme inhibitors

Angiotensin converting enzyme (ACE) inhibitors are important for the treatment of hypertension as they can decrease the formation of vasopressor hormone angiotensin II (Ang II) and elevate the levels of vasodilating hormone bradykinin. It is observed that bradykinin contains a Ser-Pro-Phe motif near the site of hydrolysis. The selenium analogues of captopril represent a novel class of ACE inhibitors as they also exhibit significant antioxidant activity. In this study, several di- and tripeptides containing selenocysteine and cysteine residues at the N-terminal were synthesized. Hydrolysis of angiotensin I (Ang I) to Ang II by ACE was studied in the presence of these peptides. It is observed that the introduction of L-Phe to Sec-Pro and Cys-Pro peptides significantly increases the ACE inhibitory activity. On the other hand, the introduction of L-Val or L-Ala decreases the inhibitory potency of the parent compounds. The presence of an L-Pro moiety in captopril analogues appears to be important for ACE inhibition as the replacement of L-Pro by L-piperidine 2-carboxylic acid decreases the ACE inhibition. The synthetic peptides were also tested for their ability to scavenge peroxynitrite (PN) and to exhibit glutathione peroxidase (GPx)-like activity. All the selenium-containing peptides exhibited good PN-scavenging and GPx activities.

Measurement and Applications of Long-Range Heteronuclear Scalar Couplings: Recent Experimental and Theoretical Developments

The use of long-range heteronuclear couplings, in association with 1H1H scalar couplings and NOE restraints, has acquired growing importance for the determination of the relative stereochemistry, and structural and conformational information of organic and biological molecules. However, the routine use of such couplings is hindered by the inherent difficulties in their measurement. Prior to the advancement in experimental techniques, both long-range homo- and heteronuclear scalar couplings were not easily accessible, especially for very large molecules. The development of a large number of multidimensional NMR experimental methodologies has alleviated the complications associated with the measurement of couplings of smaller strengths. Subsequent application of these methods and the utilization of determined J-couplings for structure calculations have revolutionized this area of research. Problems in organic, inorganic and biophysical chemistry have also been solved by utilizing the short- and long-range heteronuclear couplings. In this minireview, we discuss the advantages and limitations of a number of experimental techniques reported in recent times for the measurement of long-range heteronuclear couplings and a few selected applications of such couplings. This includes the study of medium- to larger-sized molecules in a variety of applications, especially in the study of hydrogen bonding in biological systems. The utilization of these couplings in conjunction with theoretical calculations to arrive at conclusions on the hyperconjugation, configurational analysis and the effect of the electronegativity of the substituents is also discussed.

Energy absorption behaviours of CSM-based GFRC plates with hemispherical features

In the present study, the mechanical behaviour of CSM (chopped strand mat)-based GFRC (glass fibre-reinforced composite) plates with single and multiple hemispheres under compressive loads has been investigated both experimentally and numerically. The basic stress-strain behaviours arc identified with quasi-static tests on two-ply coupon laminates and short cylinders, and these are followed up with compressive tests in a UTM (universal testing machine) on single- and multiple-hemisphere plates. The ability of an explicit LS-DYNA solver in predicting the complex material behaviour of composite hemispheres, including failure, is demonstrated. The relevance and scalability of the present class of structural components as `force-multipliers' and `energy-multipliers' have been justified by virtue of findings that as the number of hemispheres in a panel increased from one to four, peak load and average absorbed energy rose by factors of approximately four and six, respectively. The performance of a composite hemisphere has been compared to similar-sized steel and aluminium hemispheres, and the former is found to be of distinctly higher specific energy than the steel specimen. A simulation-based study has also been carried out on a composite 2 x 2-hemisphere panel under impact loads and its behaviour approaching that of an ideal energy absorber has been predicted. In summary, the present investigation has established the efficacy of composite plates with hemispherical force multipliers as potential energy-absorbing countermeasures and the suitability of CAE (computer-aided engineering) for their design.

Network properties of protein-decoy structures

Convergence of the vast sequence space of proteins into a highly restricted fold/conformational space suggests a simple yet unique underlying mechanism of protein folding that has been the subject of much debate in the last several decades. One of the major challenges related to the understanding of protein folding or in silico protein structure prediction is the discrimination of non-native structures/decoys from the native structure. Applications of knowledge-based potentials to attain this goal have been extensively reported in the literature. Also, scoring functions based on accessible surface area and amino acid neighbourhood considerations were used in discriminating the decoys from native structures. In this article, we have explored the potential of protein structure network (PSN) parameters to validate the native proteins against a large number of decoy structures generated by diverse methods. We are guided by two principles: (a) the PSNs capture the local properties from a global perspective and (b) inclusion of non-covalent interactions, at all-atom level, including the side-chain atoms, in the network construction accommodates the sequence dependent features. Several network parameters such as the size of the largest cluster, community size, clustering coefficient are evaluated and scored on the basis of the rank of the native structures and the Z-scores. The network analysis of decoy structures highlights the importance of the global properties contributing to the uniqueness of native structures. The analysis also exhibits that the network parameters can be used as metrics to identify the native structures and filter out non-native structures/decoys in a large number of data-sets; thus also has a potential to be used in the protein `structure prediction' problem.

Synthesis and spectral characterization of cyclotriphosphazene based 18-membered macrocycles

New 18-membered cyclotriphosphazene-containing macrocycles 7-10 were obtained by 1 + 1 condensation reaction of dispiro-N3P3(C12H8O2)(2)((N(Me)N=CH)(2) N4C20H26)] (2) with N,N'-dimethyl-ethylenediamine-1,4-diyldimethylenebis(4-methyl-2-formylph enol) (3), N,N'-dimethyl-ethylenediamine-1,4-diyldimethylenebis(4,5-dimethyl-2-form ylphenol) (4), N,N'-dimethyl-ethylenediamine-1,4-diyldimethylenebis(5-chloro-2-formylph enol) (5) and N,N'-dimethyl-ethylenediamine-1,4-diyldimethylenebis(5-bromo-2-formylphe nol) (6), respectively. (C) 2012 Elsevier B.V. All rights reserved.

Synthesis of benzofuran based 1,3,5-substituted pyrazole derivatives: As a new class of potent antioxidants and antimicrobials-A novel accost to amend biocompatibility

In search for a new antioxidant and antimicrobial agent with improved potency, we synthesized a series of benzofuran based 1,3,5-substituted pyrazole analogues (5a-l) in five step reaction. Initially, o-alkyl derivative of salicyaldehyde readily furnish corresponding 2-acetyl benzofuran 2 in good yield, on treatment with 1,8-diaza bicyclo5.4.0]undec-7-ene (DBU) in the presence of molecular sieves. Further, aldol condensation with vanillin, Claisen-Schmidt condensation reaction with hydrazine hydrate followed by coupling of substituted anilines afforded target compounds. The structures of newly synthesized compounds were confirmed by IR, H-1 NMR, C-13 NMR, mass, elemental analysis and further screened for their antioxidant and antimicrobial activities. Among the tested compounds 5d and 5f exhibited good antioxidant property with 50% inhibitory concentration higher than that of reference while compounds 5h and 5l exhibited good antimicrobial activity at concentration 1.0 and 0.5 mg/mL compared with standard, streptomycin and fluconazole respectively. (C) 2012 Elsevier Ltd. All rights reserved.

Synthesis and structural characterization of some trisulfide analoges of thiouracil-based antithyroid drugs

Thiourea-based antithyroid drugs are effectively used for the treatment of hyperthyroidism. In this paper, we describe the synthesis of new trisulfides (11-12) from the commonly used thiourea-based antithyroid drugs such as 6-n-propyl-2-thiouracil (PTU) and 6-methyl-2-thiouracil (MTU) in the reaction with I-2/KI system. Structural analysis by single crystal X-ray diffraction studies revealed the stabilization of trisulfides by a lactam-lactim tautomerism facilitating effective intramolecular as well as intermolecular non-covalent interactions. Although the structures of both trisulfides were found to be quite similar, a notable difference in the intermolecular interactions was observed between compounds 11 and 12 leading to different structural patterns. Structural stabilization of these trisulfides by tautomerism followed by intramolecular as well as intermolecular H-bonds makes these molecules as perfect examples in molecular recognition with self-complementary donor and acceptor units within a single molecule. (C) 2012 Elsevier B.V. All rights reserved.

Assessment of seismic hazard and liquefaction potential of Gujarat based on probabilistic approaches

Gujarat is one of the fastest-growing states of India with high industrial activities coming up in major cities of the state. It is indispensable to analyse seismic hazard as the region is considered to be most seismically active in stable continental region of India. The Bhuj earthquake of 2001 has caused extensive damage in terms of causality and economic loss. In the present study, the seismic hazard of Gujarat evaluated using a probabilistic approach with the use of logic tree framework that minimizes the uncertainties in hazard assessment. The peak horizontal acceleration (PHA) and spectral acceleration (Sa) values were evaluated for 10 and 2 % probability of exceedance in 50 years. Two important geotechnical effects of earthquakes, site amplification and liquefaction, are also evaluated, considering site characterization based on site classes. The liquefaction return period for the entire state of Gujarat is evaluated using a performance-based approach. The maps of PHA and PGA values prepared in this study are very useful for seismic hazard mitigation of the region in future.