Fragments, network biology and designing multiple ligands

Modulating multiple protein targets simultaneously can be beneficial for treating complex diseases. The redundancy that exists within biological networks means that modulating single proteins might not be sufficient to produce the desired efficacy while, at the same time, minimizing adverse effects. Designing multi-target drugs can be challenging for medicinal chemists, with current lead-discovery strategies often producing large, complex molecules with low ligand efficiency and poor oral bioavailability. Paradoxically, analyses of the relationship between the selectivity of biologically active compounds and their molecular size suggest that promiscuous compounds should typically be smaller than target-selective compounds. A fragment-based approach to multi-target drug discovery could lead to a new generation of compounds with improved physicochemical and pharmacokinetic properties.