Limits...
Multi-target pharmacology: possibilities and limitations of the "skeleton key approach" from a medicinal chemist perspective.

Talevi A - Front Pharmacol (2015)

Bottom Line: While medicinal chemists usually rely on some version of the lock and key paradigm to design novel therapeutics, modern pharmacology recognizes that the mid- and long-term effects of a given drug on a biological system may depend not only on the specific ligand-target recognition events but also on the influence of the repeated administration of a drug on the cell gene signature.The design of multi-target agents usually imposes challenging restrictions on the topology or flexibility of the candidate drugs, which are briefly discussed in the present article.Finally, computational strategies to approach the identification of novel multi-target agents are overviewed.

View Article: PubMed Central - PubMed

Affiliation: Medicinal Chemistry, Department of Biological Sciences, Faculty of Exact Sciences, National University of La Plata , La Plata, Argentina.

ABSTRACT
Multi-target drugs have raised considerable interest in the last decade owing to their advantages in the treatment of complex diseases and health conditions linked to drug resistance issues. Prospective drug repositioning to treat comorbid conditions is an additional, overlooked application of multi-target ligands. While medicinal chemists usually rely on some version of the lock and key paradigm to design novel therapeutics, modern pharmacology recognizes that the mid- and long-term effects of a given drug on a biological system may depend not only on the specific ligand-target recognition events but also on the influence of the repeated administration of a drug on the cell gene signature. The design of multi-target agents usually imposes challenging restrictions on the topology or flexibility of the candidate drugs, which are briefly discussed in the present article. Finally, computational strategies to approach the identification of novel multi-target agents are overviewed.

No MeSH data available.


Extrapolation of the classic lock and key analogy to multi-target agents.
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Figure 1: Extrapolation of the classic lock and key analogy to multi-target agents.

Mentions: Medicinal chemists usually resort to the traditional lock and key model to describe the interaction between a ligand and its molecular target (or an updated version of this paradigm that contemplates the ligand and target flexibility, such as the hand-in-glove analogy). The general idea is that the ligand (the key) and the target (the lock) should have complementary features to efficiently interact and trigger some biological response (open the lock). Frequently, different ligands can elicit a qualitatively similar response at a certain target. For different keys to activate the same lock alike they must share some common, essential arrangement of features (the blade of the key), which will be termed the pharmacophore (from the Greek, what carries the medicine). The remaining part of the key (the bow) may be indeed important, but less subject to structural restrictions (Figure 1).


Multi-target pharmacology: possibilities and limitations of the "skeleton key approach" from a medicinal chemist perspective.

Talevi A - Front Pharmacol (2015)

Extrapolation of the classic lock and key analogy to multi-target agents.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4585027&req=5

Figure 1: Extrapolation of the classic lock and key analogy to multi-target agents.
Mentions: Medicinal chemists usually resort to the traditional lock and key model to describe the interaction between a ligand and its molecular target (or an updated version of this paradigm that contemplates the ligand and target flexibility, such as the hand-in-glove analogy). The general idea is that the ligand (the key) and the target (the lock) should have complementary features to efficiently interact and trigger some biological response (open the lock). Frequently, different ligands can elicit a qualitatively similar response at a certain target. For different keys to activate the same lock alike they must share some common, essential arrangement of features (the blade of the key), which will be termed the pharmacophore (from the Greek, what carries the medicine). The remaining part of the key (the bow) may be indeed important, but less subject to structural restrictions (Figure 1).

Bottom Line: While medicinal chemists usually rely on some version of the lock and key paradigm to design novel therapeutics, modern pharmacology recognizes that the mid- and long-term effects of a given drug on a biological system may depend not only on the specific ligand-target recognition events but also on the influence of the repeated administration of a drug on the cell gene signature.The design of multi-target agents usually imposes challenging restrictions on the topology or flexibility of the candidate drugs, which are briefly discussed in the present article.Finally, computational strategies to approach the identification of novel multi-target agents are overviewed.

View Article: PubMed Central - PubMed

Affiliation: Medicinal Chemistry, Department of Biological Sciences, Faculty of Exact Sciences, National University of La Plata , La Plata, Argentina.

ABSTRACT
Multi-target drugs have raised considerable interest in the last decade owing to their advantages in the treatment of complex diseases and health conditions linked to drug resistance issues. Prospective drug repositioning to treat comorbid conditions is an additional, overlooked application of multi-target ligands. While medicinal chemists usually rely on some version of the lock and key paradigm to design novel therapeutics, modern pharmacology recognizes that the mid- and long-term effects of a given drug on a biological system may depend not only on the specific ligand-target recognition events but also on the influence of the repeated administration of a drug on the cell gene signature. The design of multi-target agents usually imposes challenging restrictions on the topology or flexibility of the candidate drugs, which are briefly discussed in the present article. Finally, computational strategies to approach the identification of novel multi-target agents are overviewed.

No MeSH data available.