Bioisostere Identification by Determining the Amino Acid Binding Preferences of Common Chemical Fragments

To assist in the structural optimization of hit/lead compounds during drug discovery, various computational approaches to identify potentially useful bioisosteric conversions have been reported. Here, the preference of chemical fragments to hydrogen bonds with specific amino acid residues was used to identify potential bioisosteric conversions. We first compiled a data set of chemical fragments frequently occurring in complex structures contained in the Protein Data Bank. We then used a computational approach to determine the amino acids to which these chemical fragments most frequently hydrogen bonded. The results of the frequency analysis were used to hierarchically cluster chemical fragments according to their amino acid preferences. The Euclid distance between amino acid preferences of chemical fragments for hydrogen bonding was then compared to MMP information in the ChEMBL database. To demonstrate the applicability of the approach for compound optimization, the similarity of amino acid preferences was used to identify known bioisosteric conversions of the epidermal growth factor receptor inhibitor gefitinib. The amino acid preference distance successfully detected bioisosteric fragments corresponding to the morpholine ring in gefitinib with a higher ROC score compared to those based on topological similarity of substituents and frequency of MMP in the ChEMBL database.