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The impact of activated c-Jun N-terminal kinase isoform JNK1 chemical pathways in insulin biosynthesis poses a potential health risk of glucose intolerance. Blocking the activity of JNK1 is a promising route for the design of anti-diabetic drugs and associated metabolic syndromes. In this study, 17 extracts of Taraxacum officinalewere chosen to bind JNK1 and ascertain their modulatory activity. We employed molecular dynamics, density functional theory and three docking approaches: standard precision, extra precision and quantum polarized ligand docking. The best binding free energy results were obtained from the quantum polarized ligand docking, with myricetin (1) showing a docking score of -10.464 kcal/mol, while quercetin (2) and daphnetin (3) displayed values of -9.769 and -7.136 kcal/mol respectively. Following this, 100 ns molecular dynamics simulations with Desmond showed stabilization average root mean square deviations of 2.34, 2.87, and 2.88 Å for myricetin, quercetin and daphnetin. Further, molecular dynamics revealed complexes of myricetin (ΔG = -38.81 kcal/mol) and quercetin (ΔG = -34.99 kcal/mol) as the most stable inside the JNK1 interface. The energy gaps for myricetin, quercetin and daphnetin were estimated to be 6.17, 6.00 and 6.53 eV employing the M06–2X functional in PCM solvation. Further, myricetin showed the strongest intramolecular hydrogen bonding with -13.06 kcal/mol. This study provides insights into possible anti-type-2 diabetes properties of Taraxacum officinaletargeting JNK1.

AbstractMycobacterium tuberculosiscell wall is intricate and impermeable to many agents. A D, D-carboxypeptidase (DacB1) is one of the enzymes involved in the biosynthesis of cell wall peptidoglycan and catalyzes the terminal D-alanine cleavage from pentapeptide precursors. Catalytic activity and mechanism by which DacB1 functions is poorly understood. Herein, we investigated the acylation mechanism of DacB1 by β-lactams using a 6-membered ring transition state model that involves a catalytic water molecule in the reaction pathway. The full transition states (TS) optimization plus frequency were achieved using the ONIOM (B3LYP/6-31 + G(d): AMBER) method. Subsequently, the activation free energies were computed via single-point calculations on fully optimized structures using B3LYP/6-311++(d,p): AMBER and M06-2X/6-311++(d,p): AMBER with an electronic embedding scheme. The 6-membered ring transition state is an effective model to examine the inactivation of DacB1 via acylation by β-lactams antibiotics (imipenem, meropenem, and faropenem) in the presence of the catalytic water. The ΔG#values obtained suggest that the nucleophilic attack on the carbonyl carbon is the rate-limiting step with 13.62, 19.60 and 30.29 kcal mol−1for Imi–DacB1, Mero–DacB1 and Faro–DacB1, respectively. The electrostatic potential (ESP) and natural bond orbital (NBO) analysis provided significant electronic details of the electron-rich region and charge delocalization, respectively, based on the concerted 6-membered ring transition state. The stabilization energies of charge transfer within the catalytic reaction pathway concurred with the obtained activation free energies. The outcomes of this study provide important molecular insight into the inactivation of D, D-carboxypeptidase by β-lactams.Communicated by Ramaswamy H. Sarma

AbstractHIV-1 protease (HIV-1 PR) is an essential enzyme for the replication process of its virus, and therefore considered an important target for the development of drugs against the acquired immunodeficiency syndrome (AIDS). Our previous study shows that the catalytic mechanism of subtype B/C-SA HIV-1 PR follows a one-step concerted acyclic hydrolysis reaction process using a two-layered ONIOM B3LYP/6-31++G(d,p) method. This present work is aimed at exploring the proposed mechanism of the proteolysis catalyzed by HIV-1 PR and to ensure our proposed mechanism is not an artefact of a single theoretical technique. Hence, we present umbrella sampling method that is suitable for calculating potential mean force (PMF) for non-covalent ligand/substrate-enzyme association/dissociation interactions which provide thermodynamic details for molecular recognition. The free activation energy results were computed in terms of PMF analysis within the hybrid QM(DFTB)/MM approach. The theoretical findings suggest that the proposed mechanism corresponds in principle with experimental data. Given our observations, we suggest that the QM/MM MD method can be used as a reliable computational technique to rationalize lead compounds against specific targets such as the HIV-1 protease.

This review describes the usefulness of in silico design approaches in the design of new radiopharmaceuticals, especially peptide-based radiotracers (including peptidomimetics). Although not part of the standard arsenal utilized during radiopharmaceutical design, the use of in silico strategies is steadily increasing in the field of radiochemistry as it contributes to a more rational and scientific approach. The development of new peptide-based radiopharmaceuticals as well as a short introduction to suitable computational approaches are provided in this review. The first section comprises a concise overview of the three most useful computeraided drug design strategies used, namely i) a Ligand-based Approach (LBDD) using pharmacophore modelling, ii) a Structure-based Design Approach (SBDD) using molecular docking strategies and iii) Absorption-Distribution-Metabolism-Excretion-Toxicity (ADMET) predictions. The second section summarizes the challenges connected to these computer-aided techniques and discusses successful applications of in silico radiopharmaceutical design in peptide-based radiopharmaceutical development, thereby improving the clinical procedure in Nuclear Medicine. Finally, the advances and future potential of in silico modelling as a design strategy is highlighted.

ABSTRACTIntroductionAntibiotic resistance caused by beta-lactamase expressing bacteria poses a concern given its global dissemination and proliferation. The emergence of the metallo beta-lactamases is an indefinite health threat toward which current antibiotics have limited clinical efficacy. One solution is to develop metallo beta-lactamase inhibitors (MBLIs) capable of restoring the activity of beta-lactam drugs.Areas coveredThis review focuses on potential metallo beta-lactamase inhibitors that have been patented during the period of 2018–2019. The aim is to provide insight into the diverse class of compounds which exhibit a synergistic inhibitory effect on carbapenem-resistant bacteria, when co-administered with a beta-lactam antibiotic.Expert opinionThe treatment strategy, of creating a broad-spectrum beta-lactamase inhibitor, is beneficial to the health sector as well as rural communities. Unfortunately, most of the inhibitors lack published data from both in vitroand in vivoevaluation, thus preventing an expert opinion on the likelihood to progress as candidates for clinical trials. From this report, the bismuth complexes, pyridinyl-nicotinamide derived sugars, boronic acid, and thiazole sulfonamide derivatives, portray promising properties for further advancement. Since there is currently no FDA approved MBLI, there remains an urgent need for the development of these combination treatment strategies.

Peptidoglycan, the exoskeleton of bacterial cell and an essential barrier that protects the cell, is synthesized by a pathway where the final steps are catalysed by transpeptidases. Knowledge of the structure and function of these vital enzymes that generate this macromolecule in M. tuberculosis could facilitate the development of potent lead compounds against tuberculosis. This review summarizes the experimental and computational studies to date on these aspects of transpeptidases in M. tuberculosis that have been identified and validated. The reported structures of L,D- and D,D-transpeptidases, as well as their functionalities, are reviewed and the proposed enzymatic mechanisms for L,D-transpeptidases are summarized. In addition, we provide bioactivities of known tuberculosis drugs against these enzymes based on both experimental and computational approaches. Advancing knowledge about these prominent targets supports the development of new drugs with novel inhibition mechanisms overcoming the current need for new drugs against tuberculosis.

Current investigations on the Human Immunodeficiency Virus Protease (HIV-1 PR) as a druggable target towards the treatment of AIDS require an update to facilitate further development of promising inhibitors with improved inhibitory activities. For the past two decades, up to 100 scholarly reports appeared annually on the inhibition and catalytic mechanism of HIV-1 PR. A fundamental literature review on the prerequisite of HIV-1 PR action leading to the release of the infectious virion is absent. Herein, recent advances (both computationally and experimentally) on the recognition mode and reaction mechanism of HIV-1 PR involving its natural targets are provided. This review features more than 80 articles from reputable journals. Recognition of the natural Gag and Gag-Pol cleavage junctions by this enzyme and its mutant analogs was first addressed. Thereafter, a comprehensive dissect of the enzymatic mechanism of HIV-1 PR on its natural polypeptide sequences from literature was put together. In addition, we highlighted ongoing research topics in which in silico methods could be harnessed to provide deeper insights into the catalytic mechanism of the HIV-1 protease in the presence of its natural substrates at the molecular level. Understanding the recognition and catalytic mechanism of HIV-1 PR leading to the release of an infective virion, which advertently affects the immune system, will assist in designing mechanismbased inhibitors with improved bioactivity.

The Human Immunodeficiency Virus type 1 (HIV-1) protease is a crucial target for HIV/AIDS treatment, and understanding its catalytic mechanism is the basis on which HIV-1 enzyme inhibitors are developed. Several experimental studies have indicated that HIV-1 protease facilitates the cleavage of the Gag and Gag-Pol polyproteins and it is highly selective with regard to the cleaved amino acid precursors and physical parameters. However, the main theoretical principles of substrate specificity and recognition remain poorly understood theoretically. By means of a one-step concerted transition state modeling, the recognition of natural substrates by HIV-1 PR subtypes (B and C-SA) was studied. This was carried out to compare the activation free energies at varying peptide bond regions (scissile and nonscissile) within the polypeptide sequence using ONIOM calculations. We studied both P3–P3′ and P5–P5′ natural substrate systems. For P3–P3′ substrates, excellent recognition was observed for the MA-CA family but not for the RH-IN substrates. Satisfactory recognition for the latter was only observed for the longer sequence (P5–P5′) after the substrate was subjected to an MD run to maximize the interaction between the enzyme and the substrate. These results indicate that both sequence and structure are important for correct scissile bond recognition of these natural substrates.

Infectious diseases are the leading cause of mortality worldwide, with viruses in particular making global impact on healthcare and socioeconomic development. In addition, the rapid development of drug resistance to currently available therapies and adverse side effects due to prolonged use is a serious public health concern. The development of novel treatment strategies is therefore required. The interaction of nanostructures with microorganisms is fast-revolutionizing the biomedical field by offering advantages in both diagnostic and therapeutic applications. Nanoparticles offer unique physical properties that have associated benefits for drug delivery. These are predominantly due to the particle size (which affects bioavailability and circulation time), large surface area to volume ratio (enhanced solubility compared to larger particles), tunable surface charge of the particle with the possibility of encapsulation, and large drug payloads that can be accommodated. These properties, which are unlike bulk materials of the same compositions, make nanoparticulate drug delivery systems ideal candidates to explore in order to achieve and/or improve therapeutic effects. This review presents a broad overview of the application of nanosized materials for the treatment of common viral infections.

C68H104O4, monoclinic, P21/n(no. 14), a= 19.4442(12) Å, b= 16.8522(11) Å, c= 38.048(3) Å, β= 92.400(1)°, V= 12456.4(14) Å3, Z= 8, Rgt(F) = 0.0488, wRref(F2) = 0.1326, T= 153 K.

A rapid and efficient diagnostic test was developed for the detection of Mycobacterium tuberculosisantigens in serum samples of active tuberculosis (TB) and extrapulmonary TB patients via a liposomal agglutination-based method.

C34H39NOSi, triclinic, P1̅ (no. 2), a= 10.0901(2) Å, b= 11.5016(2) Å, c= 14.4098(3) Å, α= 69.207(1)°, β= 86.555(2)°, γ= 65.579(3)°, V= 1416.10(6) Å3, Z= 2, Rgt(F) = 0.0463, wRref(F2) = 0.1200, T= 100(2) K.

An alarming rise of multidrug-resistant Mycobacterium tuberculosisstrains and the continuous high global morbidity of tuberculosis have reinvigorated the need to identify novel targets to combat the disease. The enzymes that catalyze the biosynthesis of peptidoglycan in M. tuberculosisare essential and noteworthy therapeutic targets. In this study, the biochemical function and homology modeling of MurI, MurG, MraY, DapE, DapA, Alr, and Ddl enzymes of the CDC1551 M. tuberculosisstrain involved in the biosynthesis of peptidoglycan cell wall are reported. Generation of the 3D structures was achieved with Modeller 9.13. To assess the structural quality of the obtained homology modeled targets, the models were validated using PROCHECK, PDBsum, QMEAN, and ERRAT scores. Molecular dynamics simulations were performed to calculate root mean square deviation (RMSD) and radius of gyration (Rg) of MurI and MurG target proteins and their corresponding templates. For further model validation, RMSD and Rg for selected targets/templates were investigated to compare the close proximity of their dynamic behavior in terms of protein stability and average distances. To identify the potential binding mode required for molecular docking, binding site information of all modeled targets was obtained using two prediction algorithms. A docking study was performed for MurI to determine the potential mode of interaction between the inhibitor and the active site residues. This study presents the first accounts of the 3D structural information for the selected M. tuberculosistargets involved in peptidoglycan biosynthesis.

The single crystal X-ray structure of the extracellular portion of the L,D-transpeptidase (ex-LdtMt2– residues 120–408) enzyme was recently reported. It was observed that imipenem and meropenem inhibit activity of this enzyme, responsible for generating L,D-transpeptide linkages in the peptidoglycan layer of Mycobacterium tuberculosis. Imipenem is more active and isothermal titration calorimetry experiments revealed that meropenem is subjected to an entropy penalty upon binding to the enzyme. Herein, we report a molecular modeling approach to obtain a molecular view of the inhibitor/enzyme interactions. The average binding free energies for nine commercially available inhibitors were calculated using MM/GBSA and Solvation Interaction Energy (SIE) approaches and the calculated energies corresponded well with the available experimentally observed results. The method reproduces the same order of binding energies as experimentally observed for imipenem and meropenem. We have also demonstrated that SIE is a reasonably accurate and cost-effective free energy method, which can be used to predict carbapenem affinities for this enzyme. A theoretical explanation was offered for the experimental entropy penalty observed for meropenem, creating optimism that this computational model can serve as a potential computational model for other researchers in the field.

C68H72O10, triclinic, P1̅ (no. 2), a= 13.3619(4) Å, b= 13.9234(4) Å, c= 16.6975(5) Å, α= 96.023(2)°, β= 104.537(1)°, γ= 105.625(1)°, V= 2845.85(15) Å3, Z= 2, Rgt(F) = 0.0491, wRref(F2)= 0.1311, T= 173 K.

The simple and practical syntheses of chiral guanidine organocatalysts and their evaluation in the asymmetric Michael addition reaction of malonates and β‐keto esters with nitro‐olefins is reported. These organocatalysts are the first of their kind based on a tetrahydroisoquinoline framework. In addition, a microwave‐assisted procedure for introducing the guanidine unit onto amino amide derivatives is reported. The chiral products were obtained with quantitative chemical efficiency (up to 99 % yield) and excellent enantioselectivity (up to 97 % ee).

The short synthesis of a series of novel chiral N‐oxideorganocatalysts and their evaluation in the asymmetric allylation reaction of aromatic and α‐β‐unsaturated aldehydes with allyltrichlorosilane is reported. These readily modifiable organocatalysts are the first of their kind based on the tetrahydroisoquinoline framework. The chiral homoallyl products were obtained with good chemical efficiency (up to 93 % yield) and high enantioselectivity (up to 91 % ee) under mild reaction conditions (23 °C).

Tetrahydroisoquinoline TIQ derivatives exhibit good biological activity. However, utilization of TIQ compounds in asymmetric catalysis is limited. This paper presents a series of TIQ derivatives in asymmetric transfer hydrogenation ATH reactions. Chiral TIQ amino alcohol ligands were synthesized and screened for the ATH reaction of aromatic ketones. The effect of a cis and transphenyl substitution at the C1position on the ligand backbone was investigated both experimentally and computationally. The results showed that the transorientation on the TIQ scaffold yields higher turnover rates with a selectivity of 94  eeobtained at room temperature with an Ru complex. The cisisomer results in a high turnover rate with no selectivity. The transisomer gave 99  eeat lower temperatures. Furthermore, it was observed that substitution at the C3α position results in a drop of the enantioselectivity and the reactivity of the catalyst.

The 37-amino acid polypeptide islet amyloid polypeptide (IAPP), or amylin, is found as amyloid aggregates in the islets of Langerhans in patients with type II diabetes. Herein, we report an efficient microwave assisted solid phase peptide synthesis of amylin (IAPP). The most efficient synthesis used double and triple couplings and 10 equiv. of amino acids. Double couplings were used for most amino acids, whereas triple couplings were utilized for amino acids in selected regions. The most effective method for formation of the disulfide bond in amylin was found to be iodine oxidation. The highest purity amylin was obtained when the crude peptide was purified with HPLC before formation of the disulfide bond. The cytotoxicity of the synthesized amylin product to RIN-5F cells was determined. The synthesized amylin exhibits an exponential increase of cytotoxicity at concentrations >35 µM. Transmission electron microscope studies of a sample of amylin shows that insoluble amyloid fibrils spontaneously formed when 45 µMsolution of synthesized amylin was incubated in a suitable buffer for 6 h. © 2010 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 94: 323–330, 2010.

C24H34N2O7, triclinic, P1̅ (no. 2), a= 9.9562(8) Å, b= 10.7465(9) Å, c= 13.7925(11) Å, α= 95.143°, β= 109.970(3)°, γ= 112.229(4)°, V= 1242.62(18) Å3, Z= 2, Rgt(F)= 0.0460, wRref(F2)= 0.1337, T= 173 K.

Abstract In an attempt to resolve a racemic mixture of a trishomocubane hydantoin, the synthesis of a pair of novel diastereomers was obtained by protecting the racemic hydantoin with chlorocarbonic acid-(-)(R)-sec-butyl ester. An achiral i-propyl ester was first used to establish the procedure. The NMR elucidation of both the chiral and achiral N-protected hydantoins is described. Some proton and carbon NMR shifts on the cage are reversed when relative small changes on the protection group are introduced. The chiral centre on the protective group induced splitting of some carbon signals in the 13C spectrum on the cage skeleton, but effective separation of the diastereomers could not be obtained. In a further attempt to demonstrate the potential use of the trishomocubane amino acid in peptide synthesis, the ethyl ester of the cage amino acid was synthesised. The structures of the amino acid derivatives were elucidated with 2D NMR techniques and the assignment of the NMR data is presented.

C37H62N4O5S, triclinic, P1¯ (no. 2), a = 10.6902(4) Å, b = 12.9126(4) Å, c = 15.1755(5) Å, a = 92.277(2)°, ß = 104.928(2)°, ? = 111.714(2)°, V = 1859.1 Å3, Z = 2, Rgt(F) = 0.0380, wRref(F2) = 0.0999, T = 173 K.

C9H6FNO2S, triclinic, P1̄ (no. 2), a= 7.2786(2) Å, b= 8.1014(3) Å, c= 16.1084(5) Å, α= 76.320(1)°, β= 87.918(1)°, γ= 80.784(1)°, V= 911.00(5) Å3, Z= 4, Rgt(F) = 0.0298, wRref(F2) = 0.0857, T= 100(2) K.

C9H13FO5S, triclinic, P1̅ (no. 2), a= 5.9390(3) Å, b= 8.1581(4) Å, c= 11.3823(8) Å, α= 89.498(3)°, β= 85.314(5)°, γ= 84.916(5)°, V= 547.48(5) Å3, Z= 2, Rgt(F) = 0.0303, wRref(F2) = 0.0811, T= 293 K.

C25H24N2O3, monoclinic, P21(no. 4), a= 9.7404(5) Å, b= 10.0985(5) Å, c= 10.7520(5) Å, β= 98.328(3)°, V= 1046.45(9) Å3, Z= 2, Rgt(F) = 0.0252, wRref(F2)= 0.0600, T= 100 K.

C15H17FN2O4, monoclinic, P21/c(no. 14), a= 12.4266(11) Å, b= 6.6865(5) Å, c= 17.1510(15) Å, β= 99.288(2)°, V= 1406.4(2) Å3, Z= 4, Rgt(F) = 0.0422, wRref(F2)= 0.1139, T= 173 K.

C16H20N2O4S, monoclinic, P21/n(no. 14), a= 9.229(2) Å, b= 16.995(4) Å, c= 11.084(3) Å, β= 99.985(11)°, V= 1712.3(8) Å3, Z= 4, Rgt(F)= 0.0393, wRref(F2)= 0.1081, T= 173.

The clinical utility of important therapeutic agents is often limited by the poor permeability of biological membranes. Cell penetrating peptides are usually employed to circumvent this challenge. This approach, coupled with gold nanoparticles, are a promising vehicle for drug delivery due to its good biocompatibility profile, negligable toxicity and possibility for multi-functionalization. Here we report the functionalization and intracellular tracking of gold nanoparticles decorated with a TAT cell penetrating peptide and a fluorescein tag in a simple, two step process. Fluorescence microscopy has confirmed the localization of the functionalized nanoparticles to be inside the cells, specifically within, or in close proximity to the nuclei of MT-4 lymphocytes; a HIV-relevant cell line in which this has not been previously demonstrated. The results of this study demonstrate that TAT has been efficiently conjugated to gold nanoparticles to facilitate both cellular and targeted nuclear entry.

Novel Lewis base N‐oxide organocatalysts possessing tetrahydroisoquinoline as a readily tunable backbone are synthesized and evaluated in asymmetric allylation reactions of aromatic and α,β‐unsaturated aldehydes.

Review: about 400 refs.

The title reaction affords high enantiomeric excesses but also a high substrate dependence is observed.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.