O-alkyl resorcarenes: where are we now?

This review describes the current position in the emerging field of direct synthesis of O-alkyl resorcarenes through the use of O-protected precursors. The use of this approach for the selective synthesis of the diastereoisomers of resorc[4]arenes, the synthesis of parent resorcarenes and pyrogalloranes and the preparation of chiral partially alkylated resorc[4]arenes are highlighted. The applications of such molecules, with regard to their role as ligand platforms, for binding of cations, organic electron acceptors and in chiral discrimination are discussed.     

Improving the intrinsic activity of electrocatalysts for sustainable energy conversion: where are we and where can we go?

As we are in the midst of a climate crisis, there is an urgent need to transition to the sustainable production of fuels and chemicals. A promising strategy towards this transition is to use renewable energy for the electrochemical conversion of abundant molecules present in the earth''s atmosphere such as H₂O, O₂, N₂ and CO₂, to synthetic fuels and chemicals. A cornerstone to this strategy is the development of earth abundant electrocatalysts with high intrinsic activity towards the desired products. In this perspective, we discuss the importance and challenges involved in the estimation of intrinsic activity both from the experimental and theoretical front. Through a thorough analysis of published data, we find that only modest improvements in intrinsic activity of electrocatalysts have been achieved in the past two decades which necessitates the need for a paradigm shift in electrocatalyst design. To this end, we highlight opportunities offered by tuning three components of the electrochemical environment: cations, buffering anions and the electrolyte pH. These components can significantly alter catalytic activity as demonstrated using several examples, and bring us a step closer towards complete system level optimization of electrochemical routes to sustainable energy conversion.

We evaluate the improvements over the past two decades in intrinsic activity of electrocatalysts for sustainable energy conversion, and highlight opportunities from tuning the electrolyte.     

A decade of yeast surface display technology: where are we now?

Yeast surface display has become an increasingly popular tool for protein engineering and library screening applications. Recent advances have greatly expanded the capability of yeast surface display, and are highlighted by cell-based selections, epitope mapping, cDNA library screening, and cell adhesion engineering. In this review, we discuss the state-of-the-art yeast display methodologies and the rapidly expanding set of applications afforded by this technology.     

An insight into iTRAQ: where do we stand now?

The iTRAQ (isobaric tags for relative and absolute quantification) technique is widely employed in proteomic workflows requiring relative quantification. Here, we review the iTRAQ literature; in particular, we focus on iTRAQ usage in relation to other commonly used quantitative techniques e.g. stable isotope labelling in culture (SILAC), label-free methods and selected reaction monitoring (SRM). As a result, we identify several issues arising with respect to iTRAQ. Perhaps frustratingly, iTRAQ's attractiveness has been undermined by a number of technical and analytical limitations: it may not be truly quantitative, as the changes in abundance reported will generally be underestimated. We discuss weaknesses and strengths of iTRAQ as a methodology for relative quantification in the light of this and other technical issues. We focus on technical developments targeted at iTRAQ accuracy and precision, use of 4-plex over 8-plex reagents and application of iTRAQ to post-translational modification (PTM) workflows. We also discuss iTRAQ in relation to label-free approaches, to which iTRAQ is losing ground.     

The impact of flow injection on modern chemical analysis: has it fulfilled our expectations? And where are we going?

Presenting a condensation of the opening lecture of the 12th ICFIA conference, this communication presents a view of the impact that flow injection analysis (FIA) has had on modern analytical chemistry, evaluated both within the academic community and outside it, i.e. in “industry”. The ensuing developments of FIA, encompassing sequential injection analysis (SIA) and bead injection lab-on-valve (BI-LOV), are described and their individual features discussed. Finally, some recent results of the activities from the author’s own research group are briefly mentioned.     

Speciation and legislation – Where are we today and what do we need for tomorrow?

In international legislation concerning trace elements in food, in the environment or in occupational health most regulations are based on the total element contents, and are frequently given as maximum limits or guideline levels. In contrast, only few regulations pay attention to the molecular species in which the elements are bound. The international legislation concerning contaminants in food is presently being established in the Codex Alimentarius, which is an independent United Nations organisation under the joint FAO/WHO Food Standards Programme. Development of the Codex General Standard for Contaminants and Toxins in Food provides the framework for future international legislation on metals as contaminants in food. For certain food additives, which include some essential minerals, speciation is an integral part of the set of specification criteria, because only certain defined chemical compounds are permitted as sources of the essential element. The development of more species-specific analytical and toxicological data, and improved communication with legislators will be necessary before it will become possible to lay down species-specific regulations in all the cases where the specialised scientist will consider it reasonable.     

Solid-phase microextraction. How far are we from clinical practice?

The current review briefly discusses the future development of solid-phase microextraction (SPME) and its potential application in the field of clinical medicine, including pharmacokinetic studies, therapeutic drug monitoring, biomarker discovery, and targeted and untargeted metabolomics. We also discuss aspects of automation and high-throughput analysis as major requirements of daily clinical practice. We give examples of clinically-validated applications of SPME and point out the regulatory restrictions limiting some in-vivo SPME studies. We briefly review the current state of progress in this extraction technique in the context of its future application in medical research and laboratory testing, including new directions (i.e. personalized medicine).     

Current trends in lead discovery: are we looking for the appropriate properties?

The new drug discovery paradigm is based on high-throughput technologies, both with respect to synthesis and screening. The progression HTS hits lead series candidate drug marketed drug appears to indicate that the probability of reaching launched status is one in a million. This has shifted the focus from good quality candidate drugs to good quality leads. We examined the current trends in lead discovery by comparing MW (molecular weight), LogP (octanol/water partition coefficient, estimated by Kowwin [17]) and LogSw (intrinsic water solubility, estimated by Wskowwin [18]) for the following categories: 62 leads and 75 drugs [11]; compounds in the development phase (I, II, III and launched), as indexed in MDDR; and compounds indexed in medicinal chemistry journals [ref. 20], categorized according to their biological activity. Comparing the distribution of the above properties, the 62 lead structures show the lowest median with respect to MW (smaller) and LogP (less hydrophobic), and the highest median with respect to LogSw (more soluble). By contrast, over 50% of the medicinal chemistry compounds with activities above 1 nanomolar have MW > 425, LogP > 4.25 and LogSw < -4.75, indicating that the reported active compounds are larger, more hydrophobic and less soluble when compared to time-tested quality leads. In the MDDR set, a progressive constraint to reduce MW and LogP, and to increase LogSw, can be observed when examining trends in the developmental sequence: phase I, II, III and launched drugs. These trends indicate that other properties besides binding affinity, e.g., solubility and hydrophobicity, need to be considered when choosing the appropriate leads.     

What are we determining using gas chromatographic multiresidue methods: tralomethrin or deltamethrin?

The analytical behaviour of the relatively new pyrethroid insecticide tralomethrin has been evaluated by using gas chromatography (GC) with electron-capture and mass spectrometry (MS) detectors, and liquid chromatography (LC)-atmospheric pressure ionization mass spectrometry with electrospray interfacing. Under the GC conditions commonly used in pesticide residue analysis, it was found that tralomethrin is transformed into deltamethrin (in a reproducible way) in the injector port of the GC system. Results obtained in this work indicate that the GC multiresidue methodologies routinely applied in the analysis of pyrethroid pesticides in foods cannot distinguish between these two pesticides, and the chromatographic signal obtained at the retention time of deltamethrin/tralomethrin can be really quantified as either deltamethrin or tralomethrin, including when it is confirmed as deltamethrin by MS. Under the LC-MS conditions assessed in this work, deltamethrin and the two diasteroisomers of tralomethrin were well separated and identified.     

A universal approach for continuum solvent pK a calculations: are we there yet?

This paper reviews several pK _a calculation strategies that are commonly used in aqueous acidity predictions. Among those investigated were the direct or absolute method, the proton exchange scheme, and the hybrid cluster–continuum (Pliego and Riveros) and implicit–explicit (Kelly, Cramer and Truhlar) models. Additionally, these protocols are applied in the pK _a calculation of 55 neutral organic and inorganic acids in conjunction with various solvent models, including the CPCM-UAKS/UAHF, IPCM, SM6 and COSMO-RS, with a view to identifying a universal approach for accurate pK _a predictions. The results indicate that the direct method is unsuitable for general pK _a calculations, although moderately accurate results (MAD <3 units) are possible for certain classes of acids, depending on the choice of solvent model. The proton exchange scheme generally delivers good results (MAD <2 units), with CPCM-UAKS giving the best performance. Furthermore, the sensitivity of this approach to the choice of reference acid can be substantially lessened if the solvation energies for ionic species are calculated via the IPCM cluster–continuum approach. Reference-independent hybrid approaches that include explicit water molecules can potentially give reasonably accurate values (MAD generally ~2 units) depending on the solvent model and the number of explicit water molecules added.     

Long-term tracking of cells using inorganic nanoparticles as contrast agents: are we there yet?

The use of inorganic nanoparticles as probes to label and track cells in vivo is already a reality. While superparamagnetic nanoparticles have been the subject of clinical studies involving magnetic resonance imaging, quantum dots and gold nanoparticles are starting to be explored for similar goals in pre-clinical studies involving fluorescence and photoacoustic imaging. Although exciting results have been obtained from in vivo investigations, there appears to be a general lack of understanding on the effects of physicochemical properties on the labelling efficiency and toxicity of those nanoparticles, as well as on their stability in the intracellular microenvironment; essential requirements for using them as probes for cellular tracking. In this tutorial review, we look at what the current literature can teach us in respect to cell interactions with these nanoparticles, with the perspective of using them as probes for cell labelling. We also examine the findings obtained in pre-clinical studies that expose potential misinterpretation that can occur when using inorganic nanoparticles for in vivo imaging.     

Polymer modeling: where has it been and where is it going?

The development of the area of polymer modeling often referred to as molecular modeling has been reviewed from its early beginnings to the present day. Key forces influencing the development include computational power, algorithmic advances and access to computational resources. The desire to apply modeling techniques to predict the properties of increasingly complex polymer-containing systems, taken in conjunction with a number of current limitations discussed in this brief review, is expected to define in part some essential future developments.     

Accuracy of enthalpy and entropy determination using the kinetic method: are we approaching a consensus?

There is an emerging consensus regarding the applicability of the kinetic method. All parties acknowledge that it is an approximate quantitative technique, capable of yielding not only enthalpy, but also entropy values. Opinions differ mainly on the accuracy of the results but it is agreed that the energy (effective temperature) dependence of kinetic method plots needs to be checked in all but the simplest of cases. When the 'apparent basicity' is found to depend on collision energy (and hence effective temperature), the extended kinetic method must be used. We have performed a large-scale modeling study, involving thousands of randomly selected molecular systems and a variety of experimental conditions, using exact calculations and realistic data sets. The results show that when the measured entropy difference between the two competing reaction channels is less than approximately 35 J mol(-1) K(-1), overall errors (standard deviations) of DeltaH(298) determined by the kinetic method are +/-5 kJ mol(-1); those of DeltaS(298) are +/-10 J mol(-1) K(-1). These include not only inherent errors of the kinetic method, but also errors in ion abundance measurement (5%) and inaccurate knowledge of reference compound thermochemistry (+/-2 kJ mol(-1), on average). We recommend, in general, that these errors be reported in kinetic method studies. When the measured entropy difference between the two competing fragmentation channels is large (>35 J mol(-1) K(-1)), it is likely to be significantly underestimated and errors of the kinetic method increase significantly.     

Hydronium ion complex of 18-crown-6: where are the protons? A density functional study of static and dynamic properties

A quantum-chemical study employing the BLYP density functional is reported for the complex of H3O+ with 18-crown-6. According to a Car-Parrinello molecular dynamics (CPMD) study at 340 K, the complex is quite flexible, and is characterized by three quasi-linear (two-center) hydrogen-bond interactions for most of the time. On a time scale of 10 ps, frequent inversions of H3O+ are observed, as well as two 120 degrees rotations switching the hydrogen bonds from one set of crown-ether O atoms to the other. These results are consistent with density-functional studies of stationary points on the potential energy surface, which show how the crown "catalyzes" the guest's inversion. Two close-lying minima are characterized, as well as two distinct transition states connecting them, either via H3O+ inversion or rotation, with barriers of 1.0 and 4.6 kcal/mol, respectively, at the BLYP/II'//BLYP/6-31G level. Orbital interactions between lone pairs on ether O atoms and hydronium sigma(OH) antibonding orbitals are important factors for the directionality of the hydrogen bonds.     

If we designed airplanes like we design drugs…

In the early days, airplanes were put together with parts designed for other purposes (bicycles, farm equipment, textiles, automotive equipment, etc.). They were then flown by their brave designers to see if the design would work—often with disastrous results. Today, airplanes, helicopters, missiles, and rockets are designed in computers in a process that involves iterating through enormous numbers of designs before anything is made. Until very recently, novel drug-like molecules were nearly always made first like early airplanes, then tested to see if they were any good (although usually not on the brave scientists who created them!). The resulting extremely high failure rate is legendary. This article describes some of the evolution of computer-based design in the aerospace industry and compares it with the progress made to date in computer-aided drug design. Software development for pharmaceutical research has been largely entrepreneurial, with only relatively limited support from government and industry end-user organizations. The pharmaceutical industry is still about 30 years behind aerospace and other industries in fully recognizing the value of simulation and modeling and funding the development of the tools needed to catch up.     

Five-coordinate Fe(III)NO and Fe(II)CO porphyrinates: where are the electrons and why does it matter?

Recent years have seen dramatic growth in our understanding of the biological roles of nitric oxide (NO). Yet, the fundamental underpinnings of its reactivities with transition metal centers in proteins and enzymes, the stabilities of their structures, and the relationships between structure and reactivity remains, to a significant extent, elusive. This is especially true for the so-called ferric heme nitrosyls ([FeNO](6) in the Enemark-Feltham scheme). The Fe-CO and C-O bond strengths in the isoelectronic ferrous carbonyl complexes are widely recognized to be inversely correlated and sensitive to structural, environmental, and electronic factors. On the other hand, the Fe-NO and N-O bonds in [FeNO](6) heme complexes exhibit seemingly inconsistent behavior in response to varying structure and environment. This report contains resonance Raman and density functional theory results that suggest a new model for FeNO bonding in five-coordinate [FeNO](6) complexes. On the basis of resonance Raman and FTIR data, a direct correlation between the nu(Fe)(-)(NO) and nu(N)(-)(O) frequencies of [Fe(OEP)NO](ClO(4)) and [Fe(OEP)NO](ClO(4)).CHCl(3) (two crystal forms of the same complex) has been established. Density functional theory calculations show that the relationship between Fe-NO and N-O bond strengths is responsive to FeNO electron density in three molecular orbitals. The highest energy orbital of the three is sigma-antibonding with respect to the entire FeNO unit. The other two comprise a lower-energy, degenerate, or nearly degenerate pair that is pi-bonding with respect to Fe-NO and pi-antibonding with respect to N-O. The relative sensitivities of the electron density distributions in these orbitals are shown to be consistent with all published indicators of Fe-N-O bond strengths and angles, including the examples reported here.     

What do we know and when do we know it?

Two essential aspects of virtual screening are considered: experimental design and performance metrics. In the design of any retrospective virtual screen, choices have to be made as to the purpose of the exercise. Is the goal to compare methods? Is the interest in a particular type of target or all targets? Are we simulating a ‘real-world’ setting, or teasing out distinguishing features of a method? What are the confidence limits for the results? What should be reported in a publication? In particular, what criteria should be used to decide between different performance metrics? Comparing the field of molecular modeling to other endeavors, such as medical statistics, criminology, or computer hardware evaluation indicates some clear directions. Taken together these suggest the modeling field has a long way to go to provide effective assessment of its approaches, either to itself or to a broader audience, but that there are no technical reasons why progress cannot be made.