Chemogenomics of Pyridoxal 5’-phosphate Dependent Enzymes

Pyridoxal 5’-phosphate dependent enzymes comprise a large protein family that plays a key role in amino acid metabolism and are structurally classified in four main fold types. PLP enzymes are acquiring an increasing interest as drug targets. For the simultaneous identification of lead compounds against either multiple or individual PLP-dependent enzymes, we have developed a chemogenomics-based approach. This approach exploits the information coded in sequences and/or structures to define ligand recognition pharmacophore models. An analysis was carried out on a dataset of 58 PLP-dependent enzyme structures determined at high resolution and comprising representative of all fold types. Evolutionarily conserved residues relevant to either coenzyme or substrate binding were identified via multiple sequence alignments and scored. Moreover, substrate binding sites were mapped on the basis of orthologous and homologous structures comparisons. Based on these analyses, pharmacophoric bi-scaffolds that are either specific for an individual enzyme or common to an enzyme sub-class were generated by linking coenzyme pharmacophores with substrate pharmacophores.