Current Pharmaceutical Design - Volume 15, Issue 6, 2009

Structural manipulation of already marketed drugs, or in general, of known biologically active compounds as a means to get novel drug candidates with improved profiles constitutes a widespread practice in medicinal chemistry. In most cases, from this approach arise novel molecules with a degree of structural complexity similar to that of the parent compound and containing a single pharmacophoric moiety aimed at hitting Read More

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. Designin Read More

The multifunctional nature of Alzheimer's disease (AD) provides the logical foundation for the development of an innovative drug design strategy centered on multi-target-directed-ligands (MTDLs). In recent years, the MTDL concept has been exploited to design different ligands hitting different biological targets. Our first rationally designed MTDL was the polyamine caproctamine (1), which provided a synergistic cholinergic actio Read More

The pharmacotherapy of complex pathological states at the cardiovascular level often requires different and complementary pharmacodynamic properties. This is frequently achieved through the administration of “cocktails”, composed by several drugs possessing different mechanisms of action. In the last years, a revision of the “one-compound-onetarget” paradigm led to a wide development of new classes of molecules, Read More

Ligands selectively targeting β -amyloid in the living brain are promising candidates of therapeutics and early diagnosis tools for Alzheimer's disease. Among the major stages of β -amyloid aggregation, monomers and oligomers are excellent targets to reduce neurotoxic brain damages for prevention of the disease progression, while oligomers and fibrils, abundant in the late stage of the disease, are pathological objectiv Read More

Polyvalency in the biological world is defined as the simultaneous binding of multiple ligands to one receptor. Polyvalency can increase the affinity of the polyvalent ligand by 100-1000 fold over the monovalent ligand. Such phenomenon has been employed to design polyvalent toxin inhibitors. Bivalency is a similar approach where two ligands are joined together with a linker to form a homo- or hetero-dimer with an increase in Read More

Recent advances in designing peptide ligands for therapeutic targets are making peptides an attractive alternative to small molecules and proteins. It is now common to see peptides developed with affinities comparable to antibodies and specificities much better than small molecules or antibodies. This is especially true in the case of tumor targeting cytotoxic drugs or targeted diagnostics where peptides can be used as a Read More

More and more evidences are still accumulating rapidly on the G-protein-coupled-receptors (GPCRs) dimerization/ oligomerization. Such common feature of GPCRs has called extensive attention to both pharmacologists and medicinal chemists for illustration of the pharmacological functions and therapeutic utilities of such receptor complex. Although there is still no clear explanation for the receptor dimerization/oligomerizati Read More

Historically treated as monomeric polypeptides, G protein-coupled receptors (GPCRs) have been shown to exist and function as constitutively formed dimers or oligomers. The quaternary structure of GPCRs may modulate ligand binding properties through allosteric mechanisms offering new opportunities for drug design by exploiting multivalency. In this context, multivalent ligands versus bivalent-ligands, possessing two Read More