High diastereoselectivity in borohydride reductions of coordinated imines.

Borohydride reduction of the imine groups in a pyruvate-derived cobalt(III) complex, (OC-6-33')-[Co(Aim(2)trien)](2)[ZnCl(4)], occurs with high diastereoselectivity. The major diastereoisomeric product, (OC-6-33'-ARSSR,CSRRS)-[Co(A(2)trien)]Cl has been isolated and crystallographically characterised. The results from base-induced isomerisation of the major isomer allow us to conclude that most of the remaining material from the reduction reactions (consisting of minor diastereoisomers) differs from the major isomer only in the relative configuration of the coordinated amines. Therefore the initial borohydride attack on the imine groups must have occurred predominantly on the same face of each imine as that which produces the major isomer. The diastereoselectivity of the reaction can be rationalised by proposing hydrogen bonding interactions between the incoming hydride reagent and other donor groups in the complex.

Discovering new classes of Brugia malayi asparaginyl-tRNA synthetase inhibitors and relating specificity to conformational change.

SLIDE software, which models the flexibility of protein and ligand side chains while docking, was used to screen several large databases to identify inhibitors of Brugia malayi asparaginyl-tRNA synthetase (AsnRS), a target for anti-parasitic drug design. Seven classes of compounds identified by SLIDE were confirmed as micromolar inhibitors of the enzyme. Analogs of one of these classes of inhibitors, the long side-chain variolins, cannot bind to the adenosyl pocket of the closed conformation of AsnRS due to steric clashes, though the short side-chain variolins identified by SLIDE apparently bind isosterically with adenosine. We hypothesized that an open conformation of the motif 2 loop also permits the long side-chain variolins to bind in the adenosine pocket and that their selectivity for Brugia relative to human AsnRS can be explained by differences in the sequence and conformation of this loop. Loop flexibility sampling using Rigidity Optimized Conformational Kinetics (ROCK) confirms this possibility, while scoring of the relative affinities of the different ligands by SLIDE correlates well with the compounds' ranks in inhibition assays. Combining ROCK and SLIDE provides a promising approach for exploiting conformational flexibility in structure-based screening and design of species selective inhibitors.