Synonymous codon bias as a basis for novel antibiotic design: from nucleotide wobble constraint to ribosomal garrotte.

Aim: The observation of low guanine frequencies at wobble position codons over Rossmann-fold GXGXXG motifs, led to the discovery of sequence-wide synonymous codon bias, from this we propose novel ribosomal inhibitors. Methodology & results: The wobble bases of multiple sequence alignments of diverse Rossmann-fold enzymes were counted, A, C, T and G wobble frequencies of consecutive codons were displayed as wobble plots. Synonymous codon constraints were found throughout the length of proteins, particularly at Rossmann folds.

Antibiotics: where to throw the spanner in the ribosomal machinery?

The sheer molecular scale of the ribosome is intimidating to the traditional drug designer. By analyzing the ribosome as a series of 12 key target sites, this review seeks to make the ribosome ligand design process more manageable. Analysis of recently evaluated ribosomal structures, particularly those with bound antibiotics, indicates where the ligand target sites are located.

Polypharmacology: in silico methods of ligand design and development.

How to design a ligand to bind multiple targets, rather than to a single target, is the focus of this review. Rational polypharmacology draws on knowledge that is both broad ranging and hierarchical. Computer-aided multitarget ligand design methods are described according to their nested knowledge level.