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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.


Multi-target antibiotic phyto-drug conjugates designed by Jayaraman et al. (2013).
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Figure 2: Multi-target antibiotic phyto-drug conjugates designed by Jayaraman et al. (2013).

Mentions: Development of tailored multi-target agents with affinity to unrelated or weakly related drug targets relies mainly in two approaches (Morphy et al., 2004; Ma et al., 2010): the methodical combination of pharmacophores from selective, single-target ligands (a fragment-based approach) and; the screening of compound collections by simultaneous application of multiple computational models (or a single, multi-tasking computational model) to identify compounds with a suitable combination of activities. In the first approximation, the distinct pharmacophores are joined together by a cleavable or stable linker or, alternatively, they are overlapped by taking advantage of structural commonalities (Morphy et al., 2004). The use of linkers often leads to compounds with unfavorable biopharmaceutic or pharmacokinetic profile (e.g., compounds that violate more than two of the Lipinski’s rules). Although the use of cleavable linkers might be advantageous, it also limits some of the merits of the multi-target approach in comparison with combination therapies (simplified pharmacokinetics, reduced chance of drug interactions). Moreover, the fragment-based approach could lead to poor ligand efficiency metrics (Hopkins et al., 2014), which refer to the binding efficiency per atom. It might be speculated that, since only a part of the molecule can interact with each of the proposed targets, the other part can become an obstacle for the binding event, reducing the binding efficiency because of enthalpic and/or entropic reasons, which is represented through the awkward topology of key number 3 (Figure 1). Therefore, the overlapping or merging approach (searching partially or highly integrated pharmacophores in a small molecule) seems more attractive from a biopharmaceutical viewpoint. Including some degree of flexibility in the molecule may help the common and non-common pharmacophoric features to accommodate to the correspondent binding sites of the different intended targets; however, the degree of flexibility should be carefully tuned so that an excess of flexibility does not conspire against the binding affinity (owing to unfavorable entropic loss associated to the binding event) or the bioavailability of the drug (it should be remembered that many druglikeness rules limit the number of flexible bonds in the molecule). An illustrative example of some of these principles is provided by the recent research from Jayaraman et al. (2013). These authors applied the fragment-based approach in the design of phytochemical-antibiotic conjugates conceived as multivalent inhibitors of Pseudomonas aeruginosa DNA gyrase subunit B (GyrB)/topoisomerase IV subunit B, dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS). Departing from previously identified pharmacophores for inhibitors of E. coli GyrB and DHFR, the authors derived a common pharmacophoric model for multi-inhibition of such enzymes. Remarkably, they decided on using simple phenols (gallic acid and protocatechuic acid, simpler structural analogs of the bivalent natural product epigallocatechin gallate) conjugated through a non-cleavable linker to sulfamethoxazole and sulfadiazine (which inhibit DHPS; Figure 2). The decision of using simple phytochemicals as departure points resulted in four drug-like compounds with acceptable computed biopharmaceutical properties, which was checked through different drug-likeness rules (Lipinski and Veber rules) and by predicting the solubility and the percentage of absorption for the designed drug candidates. Two of the candidates displayed no violation of the rule of five and Veber rules, while the remaining two showed only one violation of Lipinski rules and marginal violation of Veber rules.


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

Talevi A - Front Pharmacol (2015)

Multi-target antibiotic phyto-drug conjugates designed by Jayaraman et al. (2013).
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: Multi-target antibiotic phyto-drug conjugates designed by Jayaraman et al. (2013).
Mentions: Development of tailored multi-target agents with affinity to unrelated or weakly related drug targets relies mainly in two approaches (Morphy et al., 2004; Ma et al., 2010): the methodical combination of pharmacophores from selective, single-target ligands (a fragment-based approach) and; the screening of compound collections by simultaneous application of multiple computational models (or a single, multi-tasking computational model) to identify compounds with a suitable combination of activities. In the first approximation, the distinct pharmacophores are joined together by a cleavable or stable linker or, alternatively, they are overlapped by taking advantage of structural commonalities (Morphy et al., 2004). The use of linkers often leads to compounds with unfavorable biopharmaceutic or pharmacokinetic profile (e.g., compounds that violate more than two of the Lipinski’s rules). Although the use of cleavable linkers might be advantageous, it also limits some of the merits of the multi-target approach in comparison with combination therapies (simplified pharmacokinetics, reduced chance of drug interactions). Moreover, the fragment-based approach could lead to poor ligand efficiency metrics (Hopkins et al., 2014), which refer to the binding efficiency per atom. It might be speculated that, since only a part of the molecule can interact with each of the proposed targets, the other part can become an obstacle for the binding event, reducing the binding efficiency because of enthalpic and/or entropic reasons, which is represented through the awkward topology of key number 3 (Figure 1). Therefore, the overlapping or merging approach (searching partially or highly integrated pharmacophores in a small molecule) seems more attractive from a biopharmaceutical viewpoint. Including some degree of flexibility in the molecule may help the common and non-common pharmacophoric features to accommodate to the correspondent binding sites of the different intended targets; however, the degree of flexibility should be carefully tuned so that an excess of flexibility does not conspire against the binding affinity (owing to unfavorable entropic loss associated to the binding event) or the bioavailability of the drug (it should be remembered that many druglikeness rules limit the number of flexible bonds in the molecule). An illustrative example of some of these principles is provided by the recent research from Jayaraman et al. (2013). These authors applied the fragment-based approach in the design of phytochemical-antibiotic conjugates conceived as multivalent inhibitors of Pseudomonas aeruginosa DNA gyrase subunit B (GyrB)/topoisomerase IV subunit B, dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS). Departing from previously identified pharmacophores for inhibitors of E. coli GyrB and DHFR, the authors derived a common pharmacophoric model for multi-inhibition of such enzymes. Remarkably, they decided on using simple phenols (gallic acid and protocatechuic acid, simpler structural analogs of the bivalent natural product epigallocatechin gallate) conjugated through a non-cleavable linker to sulfamethoxazole and sulfadiazine (which inhibit DHPS; Figure 2). The decision of using simple phytochemicals as departure points resulted in four drug-like compounds with acceptable computed biopharmaceutical properties, which was checked through different drug-likeness rules (Lipinski and Veber rules) and by predicting the solubility and the percentage of absorption for the designed drug candidates. Two of the candidates displayed no violation of the rule of five and Veber rules, while the remaining two showed only one violation of Lipinski rules and marginal violation of Veber rules.

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.