Oligopeptides are the single largest class of bioactive molecules � with roles in signal transduction, structural, enzymatic and regulatory processes. There has been intense historical research in the development of peptide-derived drugs, and following this research into the depeptidisation of peptide leads. Nature has used an infinitesimally small subset of available chemical space, with ca. 20 amino acids being available to an organism. Synthetic chemists and drug discoverers have a far larger set of possible amino acids, and the exploration of the available chemical space has led us to perform a series of analyses.Firstly, we have built a comprehensive set of approved and late-stage clinical candidate peptide drugs. Within this set, we have identified both natural and unnatural amino acids, and performed an analysis of the site-specific modification (relative to N- and C- termini), and also of the physicochemical properties of theses. Then we have also analysed the peptide content of the ChEMBL database (which contains 21,844 peptides and 91,032 associated bioactivity data points). Similar decomposition of the amino acid content was performed on this set, and showed clear differences to launched and late-stage clinical peptides. We have also investigated the ligand efficiency properties of this set of bioactive peptides and found striking differences to synthetic small molecules. Finally, we have analysed a nominally comprehensive set of all possible amino acids (containing up to 13 heavy atoms from GDB-13 database). Various clusterings of the possible vs. known amino acids (in drugs, clinical candidates and the medicinal chemistry literature) were performed.

Comprehensive analysis of explored and available physicochemical space for alpha-amino acids

243rd National Meeting (2012)

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