Over the past few years, the development of drugs that bind to more than one molecular target has gained a considerable degree of attention, since they can offer several therapeutic advantages relative to ligands that are highly selective for a single target. Nevertheless, the development of multiple-binding drugs generally is rather challenging for researchers, since their design often leads to molecules characterized by poor oral bioavailability because of their high complexity and large dimension. An examination of the drug-like properties should be effected at an early stage of the drug discovery process, so that the development of molecules suffering from poor drug-likeness is suspended as soon as possible. Unfortunately, the high complexity and the large molecular size generally associated to multiple-binding drugs lead to a lower degree of drug-likeness than that found with compounds designed to hit a single biological target. Therefore, the application of druglikeness concepts in the optimization of the physicochemical properties should be helpful in the generation of new multi-target drugs with improved pharmacokinetic profiles. For example, multiple ligands of reduced size may derive from the application of a single pharmacophore that is common to two distinct targets. This approach, however, should only be employed when the two targets are very similar, such as those belonging to the same class of proteins (e.g. peptidases, bioactive amine transporters, etc.). On the other hand, if the targets are different, then two pharmacophoric motifs are usually inserted into the multiple-binding ligand; in this case, the structural dimensions of each pharmacophore should be carefully limited so that the resulting molecular combination would not cause a dramatic reduction of the drug-like properties of the resulting multiple ligand. This chapter will provide an overview of: 1) the drug-like principles and their correlation to the ADME/Tox properties; 2) the physicochemical peculiarities of multiple ligands; 3) some of the most successful strategies employed in the development of drug-like multi-target drugs.
Drug-likeness of multiple-binding drugs
MINUTOLO, FILIPPO
2010-01-01
Abstract
Over the past few years, the development of drugs that bind to more than one molecular target has gained a considerable degree of attention, since they can offer several therapeutic advantages relative to ligands that are highly selective for a single target. Nevertheless, the development of multiple-binding drugs generally is rather challenging for researchers, since their design often leads to molecules characterized by poor oral bioavailability because of their high complexity and large dimension. An examination of the drug-like properties should be effected at an early stage of the drug discovery process, so that the development of molecules suffering from poor drug-likeness is suspended as soon as possible. Unfortunately, the high complexity and the large molecular size generally associated to multiple-binding drugs lead to a lower degree of drug-likeness than that found with compounds designed to hit a single biological target. Therefore, the application of druglikeness concepts in the optimization of the physicochemical properties should be helpful in the generation of new multi-target drugs with improved pharmacokinetic profiles. For example, multiple ligands of reduced size may derive from the application of a single pharmacophore that is common to two distinct targets. This approach, however, should only be employed when the two targets are very similar, such as those belonging to the same class of proteins (e.g. peptidases, bioactive amine transporters, etc.). On the other hand, if the targets are different, then two pharmacophoric motifs are usually inserted into the multiple-binding ligand; in this case, the structural dimensions of each pharmacophore should be carefully limited so that the resulting molecular combination would not cause a dramatic reduction of the drug-like properties of the resulting multiple ligand. This chapter will provide an overview of: 1) the drug-like principles and their correlation to the ADME/Tox properties; 2) the physicochemical peculiarities of multiple ligands; 3) some of the most successful strategies employed in the development of drug-like multi-target drugs.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
