Nature Reviews: Drug Discovery
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The challenge of new drug discovery for tuberculosis.
We discuss innovations in TB drug discovery and evolving strategies to bring newer agents more quickly to patients....
Virtual screening of chemical libraries.
Virtual screening uses computer-based methods to discover new ligands on the basis of biological structures. Although widely heralded in the 1970s and 1980s, the technique has since struggled to meet its initial promise, and drug discovery remains dominated by empirical screening. Recent successes i...
Discovery of functional elements in 12 Drosophila genomes using evolutionary signatures.
We use the genomes of 12 Drosophila species for the de novo discovery of functional elements in the fly. Each type of functional element shows characteristic patterns of change, or 'evolutionary signatures', dictated by its precise selective constraints. Such signatures enable recognition of new pro...
Identification of an antimalarial synthetic trioxolane drug development candidate.
We describe how a synthetic peroxide antimalarial drug development candidate was identified in a collaborative drug discovery project....
Five identical intron positions in ancient duplicated genes of eubacterial origin.
We report the discovery of five spliceosomal introns at positions that are precisely conserved between nuclear genes for this chloroplast/cytosol enzyme pair. These data provide strong evidence in favour of the 'introns early' hypothesis, which proposes that introns were present in the earliest cell...
Type IIA topoisomerase inhibition by a new class of antibacterial agents.
We report the 2.1 Å crystal structure of a potent, new class, broad-spectrum antibacterial agent in complex with Staphylococcus aureus DNA gyrase and DNA, showing a new mode of inhibition that circumvents fluoroquinolone resistance in this clinically important drug target. The inhibitor ‘bridge...
Small molecule inhibition of the KRAS-PDEδ interaction impairs oncogenic KRAS signalling.
We report that interfering with binding of mammalian PDEδ to KRAS by means of small molecules provides a novel opportunity to suppress oncogenic RAS signalling by altering its localization to endomembranes. Biochemical screening and subsequent structure-based hit optimization yielded inhibitors of t...
Discovery of new enzymes and metabolic pathways by using structure and genome context.
We and others are developing computation-guided strategies for functional discovery with 'metabolite docking' to experimentally derived or homology-based three-dimensional structures. Bacterial metabolic pathways often are encoded by 'genome neighbourhoods' (gene clusters and/or operons), which can...
Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants.
We resequenced 15,336 genes in 6,515 individuals of European American and African American ancestry and inferred the age of 1,146,401 autosomal single nucleotide variants (SNVs). We estimate that approximately 73% of all protein-coding SNVs and approximately 86% of SNVs predicted to be deleterious a...
High-throughput screening for drug discovery.
Recent progress in elucidating the mechanisms underlying human disease has dramatically increased the number of protein targets available for potential drug treatment. Concurrently, new approaches have increased the number of compounds that can be tested for activity against these targets. Together,...