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Multi-target directed ligands are drugs with two or more pharmacophores, which are structurally overlapping, or separated, by a spacer, in a single molecule. For example, the different ligands in MTDLs cannot have different pharmacokinetics leading to complex dosing and poor patient compliance.

Due to the complexity of multifactorial diseases, single-target drugs do not always have satisfactory efficacy. Recently, increasing evidence shows that simultaneous modulation of multiple targets may improve both therapeutic safety and efficacy, compared with single-target drugs. However, few multitarget drugs are on market or in clinical trials, despite the best efforts of medicinal chemists. 

Among the certain drug discovery methods, a very promising modern approach consists in designing multi-target-directed ligands (MTDLs). This methodology has been specifically developed for treatment of disorders with complex pathological mechanisms. 

The philosophy of one molecule-one target-one disease” was the dominant approach in medicinal chemistry for several decades up till the end of the twentieth century. This strategy was based on the identification and optimization of small chemical entities able to recognize specifically one target, believed to be fully responsible for a certain disease. The aim of the “one drug-one target” approach was to find bioactive compounds endowed with a limited risk of off-target properties, many times responsible for drug side-effects. This philosophy started to change in the last 20 years due to the emergent growing awareness that drugs designed to act on individual molecular targets are usually inadequate for multigenic diseases such as cancer, neurodegenerative, and infectious diseases. Nowadays, so-called “drug-cocktails” are often the only available approaches to pharmacologically treat many of these pathologies, with concerns related to drug-drug interactions as well as to patients’ compliance. Therefore, a special issue dedicated to collect research activities from critical areas for the development of novel multi-target-directed ligands (MTDL) through the close cooperation among pharmacologists, biochemists, medicinal chemists, and toxicologists, has been proposed. 

ADME properties showed good pharmacokinetic profiles of some compounds investigated. The ability to use the tools for the identification of interesting trends opens up new opportunities for understanding the factors affecting drug performance and for designing new drugs. 

A new computer program DESIGN has been developed for optimization of ligand binding experiments to minimize the “average” uncertainty in all unknown parameters for multiligand targets. Some of the advanced features of the program DESIGN include;

  • simultaneous optimization of two or more binding competition curves 
  • optimization of a “multiligand” experiment 

Multiligand designs are those which use combinations of two (or more) ligands in each reaction tube. Such designs are an important and natural extension of the popular method of “blocking experiments” where an additional ligand is used to suppress one or more classes of sites. The use of DESIGN in conjunction with multiligand experiments can improve the efficiency of estimation of the binding parameters, potentially resulting in reduction of the number of observations needed to obtain a desired degree of precision in representative cases.

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