The Role of Medical Structural Genomics in Discovering New Drugs for Infectious Diseases
Figure 1
Conceptual organization of the deCODE biostructures Fragments of Life library.
The current ∼1,400-compound library contains chemically tractable natural small molecule metabolites (FOL-Nat), metabolite-like compounds and their bioisosteres (FOL-NatD), and biaryl mimetics of protein architecture (FOL-Biaryl). The FOL-Nat members include any natural molecule of molecular weight <350 daltons that exists as a substrate, natural product, or allosteric regulator of any metabolic pathway in any cell type, such as the biosynthetic pathways for the neurotransmitter serotonin (1) and the plant hormone auxin (2). The FOL-Nat members also include secondary metabolites such as bestatin (3), a secondary metabolite of Streptomyces olivoreticuli [38]. FOL-NatD fragments are defined as heteroatom-containing derivatives, isosteres, or analogs of any FOL-Nat molecule. For example, fragments 4–7 contain the indole scaffold, which is known to be a privileged building block for drug molecules [39]. To emulate protein architecture, the FOL-Biaryl fragments were selected from a variety of biaryl compounds that are potential mimics of protein α, β, or γ turns [40]–[42]. These include a compound (8) whose structure in an energy-minimized state can be seen to mimic the architecture on an α-turn of a protein structure (here, residues Ser65-Ile66-Leu67-Lys68 of PDB ID:1RTP) and, similarly, a compound (9) whose structure mimics the β-turn of a protein structure (residues Ala20-Ala21-Asp22-Ser23).