Meet the Medicines-A Crowdsourced Approach to Collecting and Communicating Information about Essential Medicines Online.

The World Health Organization (WHO) maintains a list of medicines and medical devices, essential medicines, that should be available to everyone, to form a functioning healthcare system. Yet, many of these medicines remain out of reach for people around the world. One significant barrier to improving the accessibility of essential medicines is a paucity of information about both the extent and causes of this problem. E$$ENTIAL MEDICINE$ (E$$) is a citizen science project designed to investigate this deficit of information by recruiting members of the public to find, validate, compile and share information on essential medicines through an open, online database. Herein, we report an approach to crowdsourcing both the collection of information on the accessibility of essential medicines and the subsequent communication of these findings to diverse audiences. The Meet the Medicines initiative encourages members of the public to share information from the E$$ database, in a short video format appropriate for social media. This communication details the design and implementation of our crowdsourced approach and strategies for recruiting and supporting participants. We discuss data on participant engagement, consider the benefits and challenges of this approach and suggest ways to promote crowdsourcing practices for social and scientific good.

Manipulation of N-heterocyclic carbene reactivity with practical oriented electric fields.

Using density functional theory (DFT) calculations, we demonstrate that the organocatalytic properties of NHCs, such as their nucleophilicity, electrophilicity and singlet triplet gaps, are predictably influenced by electric fields. These electric fields can be delivered in practical systems using charged functional groups to provide designed local electric fields, and their effects are strong enough to be synthetically relevant even in relatively polar solvents. We also show that these electrostatically enhanced NHCs elicit dramatic changes in the energetics of key transition states of a model benzoin condensation in various solvents, which can be tuned by the sign of the applied charge and the solvent polarity. Based on these findings, we suggest that NHCs are plausible candidates for electrostatic catalysts, and that electric field effects should be considered when designing NHC frameworks.

Tuning Photoenolization-Driven Cycloadditions Using Theory and Spectroscopy.

The first broad spectrum investigation into the photoenolization/Diels-Alder (PEDA) sequence was carried out using M06-2X/6-31+G(d,p) in conjunction with SMD solvation and supported by experimental UV-vis spectroscopy. A test set of 20 prodienes was chosen to examine the role of the H atom acceptor group (substituted and unsubstituted carbonyl, thiocarbonyl, and imine), the H atom donor group, and bystander ring substituents. As reaction partners for the photogenerated dienes, a diverse test set of 20 dienophiles was examined, comprising electron rich, electron poor, neutral, strain activated, hydrocarbon, and heteroatom-containing molecules including CO2 and CO. A key finding of this work is the demonstration that the PEDA sequence of carbonyl based prodienes is tolerant of most substitution patterns. Another is that thiocarbonyl derivatives should behave analogously to the carbonyls but are likely to do so much more slowly, due to an inefficient intersystem crossing, an endothermic 1,5-hydrogen atom transfer (HAT) step, and a [1,5] sigmatropic H shift to regenerate the starting material that outcompetes the [4 + 2]cycloaddition. In contrast, the T1 state of the ortho-alkyl imines displays the incorrect orbital symmetry for 1,5-HAT and is correspondingly accompanied by higher barriers, even in the excited state. However, provided these barriers can be overcome, the remaining steps in the PEDA sequence are predicted to be facile. The Diels-Alder reaction is predicted to be of much broader scope than reported synthetic literature: while electron poor dienophiles are expected to be the most reactive partners, ethylene and electron rich alkenes should react at a synthetically useful rate. CO is predicted to undergo a facile (4 + 1)cheletropic addition instead of the normal [4 + 2]cycloaddition pathway. This unique photoenolization/cheletropic addition (PECA) sequence could provide metal-free access to benzannelated cyclopentanones.

Redox Isomerization/(3+2) Allenoate Annulation by Auto-Tandem Phosphine Catalysis.

A phosphine-catalyzed approach to pyrrolines has been developed that involves two mechanistically unlinked catalytic processes. The first involves the redox isomerization of amino crotonates to provide access to aliphatic tosyl imines, which then engage in a (3+2) annulation with various allenoates. The reaction shows generality, with 24 examples established, along with a low yielding and moderately enantioselective variant. Mechanistic studies indicate that the viability of the process is linked to the selection of catalysts with similar propensity to add to the two coupling partners.

An alternate covalent form of platelet αIIbß3 integrin that resides in focal adhesions and has altered function.

The αIIbß3 integrin receptor coordinates platelet adhesion, activation, and mechanosensing in thrombosis and hemostasis. Using differential cysteine alkylation and mass spectrometry, we have identified a disulfide bond in the αIIb subunit linking cysteines 490 and 545 that is missing in ∼1 in 3 integrin molecules on the resting and activated human platelet surface. This alternate covalent form of αIIbß3 is predetermined as it is also produced by human megakaryoblasts and baby hamster kidney fibroblasts transfected with recombinant integrin. From coimmunoprecipitation experiments, the alternate form selectively partitions into focal adhesions on the activated platelet surface. Its function was evaluated in baby hamster kidney fibroblast cells expressing a mutant integrin with an ablated C490-C545 disulfide bond. The disulfide mutant integrin has functional outside-in signaling but extended residency time in focal adhesions due to a reduced rate of clathrin-mediated integrin internalization and recycling, which is associated with enhanced affinity of the αIIb subunit for clathrin adaptor protein 2. Molecular dynamics simulations indicate that the alternate covalent form of αIIb requires higher forces to transition from bent to open conformational states that is in accordance with reduced affinity for fibrinogen and activation by manganese ions. These findings indicate that the αIIbß3 integrin receptor is produced in various covalent forms that have different cell surface distribution and function. The C490, C545 cysteine pair is conserved across all 18 integrin α subunits, and the disulfide bond in the αV and α2 subunits in cultured cells is similarly missing, suggesting that the alternate integrin form and function are also conserved.

Five Step Total Synthesis of Lythranidine.

A concise synthesis of the alkaloid lythranidine is reported. The strategy exploits the target's local C2 symmetry by adopting a two directional synthetic approach, first in an acyclic environment, then in a cyclic system and finally in a bridged macrocyclic domain. The latter phase of the synthesis, which installs all four stereocenters, involves a thermodynamically controlled, twofold intermolecular/transannular aza-Michael addition and a twofold hydride reduction. The synthesis is one third of the length of the most step-economic previous approach, providing access to gram quantities of the natural product. The broad-spectrum nature of the synthesis is demonstrated through the preparation of three diastereomeric analogues of the natural product.

Simple acyclic molecules containing a single charge-assisted O-H group can recognize anions in acetonitrile : water mixtures.

Hydroxypyridinium and hydroxyquinolinium compounds containing acidic O-H groups attached to a cationic aromatic scaffold were synthesized, i.e. N-methyl-3-hydroxypyridinium (1+) and N-methyl-8-hydroxyquinolinium (2+). These very simple compounds are capable of binding to chloride very strongly in CD3CN and with moderate strength in 9 : 1 CD3CN : D2O. Comparison with known association constants reveals that 1+ and 2+ bind chloride in CD3CN or CD3CN : D2O with comparable affinities to receptors containing significantly more hydrogen bond donors and/or higher positive charges. Crystal structures of both compounds with coordinating anions were obtained, and feature short O-Hanion hydrogen bonds. A receptor containing two hydroxyquinolinium groups was also prepared. While the low solubility of this compound caused difficulties, we were able to demonstrate chloride binding in a competitive 1 : 1 CD3CN : CD3OD solvent mixture. Addition of sulfate to this compound results in the formation of a crystallographically-characterised solid state anion coordination polymer.

A multifunctional surfactant catalyst inspired by hydrolases.

The remarkable power of enzymes to undertake catalysis frequently stems from their grouping of multiple, complementary chemical units within close proximity around the enzyme active site. Motivated by this, we report here a bioinspired surfactant catalyst that incorporates a variety of chemical functionalities common to hydrolytic enzymes. The textbook hydrolase active site, the catalytic triad, is modeled by positioning the three groups of the triad (-OH, -imidazole, and -CO2H) on a single, trifunctional surfactant molecule. To support this, we recreate the hydrogen bond donating arrangement of the oxyanion hole by imparting surfactant functionality to a guanidinium headgroup. Self-assembly of these amphiphiles in solution drives the collection of functional headgroups into close proximity around a hydrophobic nano-environment, affording hydrolysis of a model ester at rates that challenge α-chymotrypsin. Structural assessment via NMR and XRD, paired with MD simulation and QM calculation, reveals marked similarities of the co-micelle catalyst to native enzymes.

Oriented Internal Electrostatic Fields Cooperatively Promote Ground- and Excited-State Reactivity: A Case Study in Photochemical CO2 Capture.

Oriented electrostatic fields can exert catalytic effects upon both the kinetics and the thermodynamics of chemical reactions; however, the vast majority of studies thus far have focused upon ground-state chemistry and rarely consider any more than a single class of reaction. In the present study, we first use density functional theory (DFT) calculations to clarify the mechanism of CO2 storage via photochemical carboxylation of o-alkylphenyl ketones, originally proposed by Murakami et al. (J. Am. Chem. Soc. 2015, 137, 14063); we then demonstrate that oriented internal electrostatic fields arising from remote charged functional groups (CFGs) can selectively and cooperatively promote both ground- and excited-state chemical reactivity at all points along the revised mechanism, in a manner otherwise difficult to access via classical substituent effects. What is particularly striking is that electrostatic field effects upon key photochemical transitions are predictably enhanced in increasingly polar solvents, thus overcoming a central limitation of the electrostatic catalysis paradigm. We explain these observations, which should be readily extendable to the ground state.

Multidrug Resistance in Neisseria gonorrhoeae: Identification of Functionally Important Residues in the MtrD Efflux Protein.

A key mechanism that Neisseria gonorrhoeae uses to achieve multidrug resistance is the expulsion of structurally different antimicrobials by the MtrD multidrug efflux protein. MtrD resembles the homologous Escherichia coli AcrB efflux protein with several common structural features, including an open cleft containing putative access and deep binding pockets proposed to interact with substrates. A highly discriminating N. gonorrhoeae strain, with the MtrD and NorM multidrug efflux pumps inactivated, was constructed and used to confirm and extend the substrate profile of MtrD to include 14 new compounds. The structural basis of substrate interactions with MtrD was interrogated by a combination of long-timescale molecular dynamics simulations and docking studies together with site-directed mutagenesis of selected residues. Of the MtrD mutants generated, only one (S611A) retained a wild-type (WT) resistance profile, while others (F136A, F176A, I605A, F610A, F612C, and F623C) showed reduced resistance to different antimicrobial compounds. Docking studies of eight MtrD substrates confirmed that many of the mutated residues play important nonspecific roles in binding to these substrates. Long-timescale molecular dynamics simulations of MtrD with its substrate progesterone showed the spontaneous binding of the substrate to the access pocket of the binding cleft and its subsequent penetration into the deep binding pocket, allowing the permeation pathway for a substrate through this important resistance mechanism to be identified. These findings provide a detailed picture of the interaction of MtrD with substrates that can be used as a basis for rational antibiotic and inhibitor design.IMPORTANCE With over 78 million new infections globally each year, gonorrhea remains a frustratingly common infection. Continuous development and spread of antimicrobial-resistant strains of Neisseria gonorrhoeae, the causative agent of gonorrhea, have posed a serious threat to public health. One of the mechanisms in N. gonorrhoeae involved in resistance to multiple drugs is performed by the MtrD multidrug resistance efflux pump. This study demonstrated that the MtrD pump has a broader substrate specificity than previously proposed and identified a cluster of residues important for drug binding and translocation. Additionally, a permeation pathway for the MtrD substrate progesterone actively moving through the protein was determined, revealing key interactions within the putative MtrD drug binding pockets. Identification of functionally important residues and substrate-protein interactions of the MtrD protein is crucial to develop future strategies for the treatment of multidrug-resistant gonorrhea.

A pH-Switchable Electrostatic Catalyst for the Diels-Alder Reaction: Progress toward Synthetically Viable Electrostatic Catalysis.

Density functional theory calculations at the SMD/M06-2X/6-31+G(d,p)//M06-2X/6-31G(d) level of theory have been used to computationally design and test a pH-switchable electrostatic organocatalyst for Diels-Alder reactions. The successful catalyst design, bis(3-(3-phenylureido)benzyl)ammonium, was studied for the reaction of p-quinone with range of cyclic, heterocyclic, and acyclc dienes and also the reaction of cyclopentadiene with maleimide and N-phenylmaleimide. All reactions showed significant enhancements in catalysis (10-32 kJ mol-1 in barrier lowering) when the catalyst was protonated, consistent with electrostatic stabilization of the transition state. Electrostatic effects were found to diminish in polar solvents but were predicted to remain significant in nonpolar solvents.

Is protein structure enough? A review of the role of lipids in SLC6 transporter function.

SLC6 neurotransmitter transporters facilitate the Na+- and Cl--dependent uptake of amino acids and amino acid derivatives into cells. Disrupting transport leads to a range of neurological disorders. However, the SLC6 substrate transport mechanism is a topic of ongoing debate. Here, we review the prominent SLC6 substrate transport mechanisms through the lens of molecular dynamics simulations. SLC6 transporters are membrane proteins, yet their transport mechanism(s) have largely been studied without considering the impacts of synaptic lipid composition, or endogenous lipid modulators, on transporter structure and function. In this review, we highlight the importance of studying membrane transporters in an appropriate membrane model, and present opportunities for the community to glean understanding and insight into SLC6 transporter structure and function-in particular transport mechanism(s)-when both membrane lipids and endogenous lipid modulators are considered.