Articles in 2018

Ghotas Evindar, Chemistry Group Leader at GlaxoSmithKline, talks with Nature Chemistry about the advantages of using encoded libraries in drug discovery and the challenges these technologies present.

Certain drug targets have been deemed undruggable because of the difficulty in finding pharmacologically useful inhibitors. Now, two teams have developed exciting technologies for the creation of diverse collections of macrocyclic molecules and have demonstrated their usefulness for discovering macrocyclic inhibitors.

Kit Chapman explores the voyage to the discovery of element 118, the pioneer chemist it is named after, and false claims made along the way.

Nearly two decades after its discovery, the Ru(II)-catalysed C–H arylation of N-chelating aromatics with aryl halides was reinvestigated and a new key reaction intermediate was uncovered. A thorough mechanistic elucidation has now led to the development of a new class of catalysts with unique efficacy towards late-stage arylation of ‘real-world’ compounds.

The [4Fe4S]²⁺ cluster-containing DNA-repair enzyme MUTYH helps safeguard the integrity of Watson–Crick base pairing and the human genetic code. The MUTYH [4Fe4S]²⁺ cluster mediates DNA redox signalling and DNA lesion identification. Now, a MUTYH pathologic variant associated with catastrophic [4Fe4S]²⁺ cluster redox degradation, impairment of DNA signalling and human colonic tumorigenesis has been identified.

Enzymes are powerful catalysts for chemical synthesis because they are capable of providing unparalleled levels of selectivity; however, in nature they only catalyse a limited collection of reactions. Now, it has been shown that non-natural reactions that proceed via free-radical intermediates can be catalysed with high selectivity by using an exogenous photoredox catalyst in conjunction with enzymes.

Metal-catalysed enantioselective fluorination of C(sp³)–H bonds is an attractive method for preparing chiral organofluorines, but the challenge of achieving both enantioselectivity and reductive elimination selectivity remains unsolved. Now, it has been demonstrated that a chiral amino amide transient directing group can serve as a ligand for a palladium catalyst that promotes both enantioselective C(sp³)–H insertion and C(sp³)–F-selective reductive elimination.

Understanding the mechanism of photoconversion in fluorescent proteins is essential to optimizing applications in imaging and optogenetics. It has now been demonstrated that photoconversion in the photoswitchable protein dronpa follows a multi-step mechanism, with both chromophore and protein structural dynamics occurring on multiple timescales from picoseconds to hundreds of microseconds.

Biominerals feature unique and potentially useful three-dimensional structures but are often difficult to transform into functional materials. Now, a two-step ion exchange/insertion reaction has been shown to convert synthetic carbonate salts and calcium carbonate biominerals into lead halide perovskites with tunable optoelectronic properties while preserving the shapes and microstructures of the precursors.

Pyrrolysyl-tRNA synthetase(PylRS)/^PyltRNA_CUA pairs that lack the N-terminal domain but are active and orthogonal are discovered, and pairs that are mutually orthogonal to existing PylRS/^PyltRNA_CUA pairs are developed. Mutually orthogonal PylRS/^PyltRNA pairs are combined to genetically encode the incorporation of distinct ncAAs into proteins synthesized in E. coli.

As the most abundant class of biomolecules on Earth, carbohydrates are implicated in a multitude of biological functions. Now, a simple chemical transformation has enabled the direct and selective installation of carbohydrates onto a diverse range of small molecules and peptides.

Molecular vibrations can be highly effective promoters of gas-phase chemistry. Now, measurements show that excited vibrational states can survive on metal surfaces far longer than expected — reshaping our understanding of how vibrational excitation might also promote or modify heterogeneously catalysed chemistry on metals.

The beauty and activity of enzymes inspire chemists to tailor new and better non-biological catalysts. Now, a study reveals that the active sites within heterogeneous catalysts actively cooperate in a fashion phenomenologically similar to, but mechanistically distinct, from enzymes.

Scientists take nomenclature seriously, but tritium was named in a casual aside. Brett F. Thornton and Shawn C. Burdette discuss the heavy, radioactive hydrogen isotope that is available for purchase online.

Isolable compounds displaying new fundamental forms of conformational isomerism were last discovered in 1914 (atropisomerism) and 1961 (hindered pyramidal inversion). Now, a new form—referred to as akamptisomerism—has been described through four resolved stereoisomers of a transoid (BF)O(BF)-quinoxalinoporphyrin compound. The stereodescriptors parvo and amplo, necessary for their classification, have also been introduced.

The implications of coherence signals for the transfer of energy within the Fenna–Matthews–Olson complex of photosynthetic green sulfur bacteria is a well debated topic. Now, polarization-controlled 2D spectroscopy — aided by vibronic exciton modelling — has enabled the characterization of all such coherences and determination of their physical origins; while electronic coherences dephase extremely rapidly, ground- and excited-state vibrational coherences dominate.

Mixed quantum–classical molecular dynamics simulations of Na₂ in liquid tetrahydrofuran have revealed that when local specific interactions between a solute and solvent are energetically on the same order as a hydrogen bond, the solvent controls not only bond dynamics but also the chemical identity of simple solutes.

A new concept for targeted drug delivery based on enrichment triggered prodrug activation has been developed. Without enrichment, the activation reaction is sluggish; however, following enrichment, the increased concentration enhances the activation reaction rate, thereby leading to the release of the payload. The same approach can be used in antibody–drug conjugate applications.

An effective antiviral against the common cold could prevent exacerbations in asthma and chronic obstructive pulmonary disease, but the diversity and adaptability of the virus makes it a highly challenging target. Now, picomolar inhibitors of a human lipid transferase have been developed. Targeting this human lipid transferase could provide an effective and broad-spectrum approach to block viral replication in the host.