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It has been widely recognised over the recent years that parallel modulation of multiple biological targets can be beneficial for treatment of diseases with complex etiologies such as cancer asthma, and psychiatric disease. In this article, current strategies for the generation of ligands with a specific multi-target profile (designed multiple ligands or DMLs) are described and a number of illustrative example are given. Designing multiple ligands is frequently a challenging endeavour for medicinal chemists, with the need to appropriately balance affinity for 2 or more targets whilst obtaining physicochemical and pharmacokinetic properties that are consistent with the administration of an oral drug. Given that the properties of DMLs are influenced to a large extent by the proteomic superfamily to which the targets belong and the lead generation strategy that is pursued, an early assessment of the feasibility of any given DML project is essential.

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.

Increasingly, it is being recognised that a balanced modulation of several targets can provide a superior therapeutic effect and side effect profile compared to the action of a selective ligand. Rational approaches in which structural features from selective ligands are combined have produced designed multiple ligands that span a wide variety of targets and target classes. A key challenge in the design of multiple ligands is attaining a balanced activity at each target of interest while simultaneously achieving a wider selectivity and a suitable pharmacokinetic profile. An analysis of literature examples reveals trends and insights that might help medicinal chemists discover the next generation of these types of compounds.