Background: In contrast to the one target-one drug paradigm, multi-target agents seem as a promising
alternative to manage complex disorders and health conditions linked to drug resistance issues. In fact, many longstanding
drugs are in fact unintended multi-functional therapeutics that have emerged from phenotypic screening.
The last two decades, however, have witnessed the emergence of tailored multi-target agents, which according to
our perspective combine the best aspects of target-based and phenotypic-based drug discovery. Methods: We discuss
a number of considerations related to the design, screening and computer-aided discovery of multi-targeted
drugs, along with overlooked advantages that this type of agents might have in clinical trials. A theoretic example
is included to explain the reduced positive predictive value in virtual screening campaigns focused on multi-target
agents. Conclusion: Multi-target agents present great therapeutic potential for the treatment of complex health conditions
and the solution of drug resistance phenomena. However, they are certainly challenging for computer-aided drug discovery approaches. Merged or
overlapping pharmacophores should be preferred whenever possible. It is thus suggested to perform a careful selection of the combination of pursued
targets, preferring target combinations supported by co-evolution or similar biding sites.
Keywords: Tailored multi-target agents, virtual screening, drug design, in silico screening, binding efficiency metrics, drug resistance,
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