Check out Galen’s latest work on the computational design of reversible covalent picomolar inhibitors of carboxylesterase αE7 – helping to overcome insecticide resistance! The manuscript ‘Overcoming insecticide resistance through computational inhibitor design’ is now available as a preprint on bioRxiv! In this work, done in collaboration with the London lab at the Weizmann Institute of Science, we use covalent computational design to produce nano/pico-molar boronic acid inhibitors of the carboxylesterase αE7 from the agricultural pest Lucilia cuprina, as well as a common Gly137Asp αE7 mutant that confers OP resistance. These inhibitors, with no intrinsic apparent toxicity, act synergistically with the OPs diazinon and malathion to reduce the amount of OP required to kill L. cuprina by up to 16-fold, and abolish resistance. These compounds represent a solution to insecticide resistance. Shoo fly!
Nick, Paul and Colin contributed to the recently accepted paper “The Synthesis of Certain Derivatives and Analogues of (–)- and (+)-Galanthamine and an Assessment of their Capacities to Inhibit Acetylcholine Esterase” in The Journal of Organic Chemistry. This work, done in collaboration with the Banwell group at ANU, describes the syntheses of certain di- and mono-oxygenated derivatives and analogues of the alkaloid galanthamine. In contrast to results from docking studies, we show that none of these compounds strongly bind to acetylcholine esterase.
Congratulations to Paul, Galen and Colin for their work on the paper “Total Syntheses of the Amaryllidaceae Alkaloids Zephycandidine III and Lycosinine A and Their Evaluation as Inhibitors of Acetylcholinesterase”, which was recently accepted to the European Journal of Organic Chemistry. This collaboration with the Banwell Group (ANU) describes the total synthesis of the amaryllidaceae alkaloids Zephycandidine III and Lycosinine A. Contrary to an earlier study, these compounds are shown to be poor inhibitors of acetylcholinesterase.
Joe and Matt recently presented their work at the Biomolecular Machines Conference in Banff, Canada. Joe was awarded the prize for the best student talk at the conference. Joe and Matt will be spending the next few weeks working in Nobu Tokuriki’s lab at the University of British Columbia.
Colin, Thanavit, Blair and Brendon contributed to the recently published paper entitled “Mycobacterial F420H2-dependent reductases promiscuously reduce diverse compounds through a common mechanism” in Frontiers in Microbiology. This work presents the first broad survey of actinobacterial F420H2-dependent reductases as potential industrial biocatalysts by exploring the extent, as well as mechanistic and structural bases, of their substrate promiscuity. The findings of this work suggest that engineered actinobacterial F420H2-dependent reductases are promising novel biocatalysts for the facile transformation of a wide range of α,β-unsaturated compounds. Top work guys!
|Congratulations to Elena, on the publication of her paper ‘Constrained evolution of a bispecific enzyme: lessons for biocatalyst design’ in Organic and Biomolecular Chemistry. In this work we investigate the impact of intramolecular epistasis on the evolution of atrazine-specific and atrazine/ametryn bispecific triazine hydrolyses (TrzN). Results show that many of the evolutionary trajectories linking the mono-functional and bispecific isoforms are unviable due to inactive intermediates, with the epistatic interactions between mutations being responsible for the bottlenecks in the evolutionary landscape. This work will help guide future work in the design of biocatalysts.|