Limits...
Bioisosteric matrices for ligands of serotonin receptors.

Warszycki D, Mordalski S, Staroń J, Bojarski AJ - ChemMedChem (2015)

Bottom Line: Analysis of a collection of over 1 million bioisosteres of compounds with measured activity towards serotonin receptors revealed that an average of 31 % of the ligands for each target are mutual bioisosteres.In addition, the collected dataset allowed the development of bioisosteric matrices-qualitative and quantitative descriptions of the biological effects of each predefined type of bioisosteric substitution, providing favored paths of modifying the compounds.The concept exemplified here for serotonin receptor ligands can likely be more broadly applied to other target classes, thus representing a useful guide for medicinal chemists designing novel ligands.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Kraków (Poland).

Show MeSH
All bioisosteric replacements for 5-HT6R ligands belonging to A) halogen, B) phenyl, C) hydroxyl, D) amide, and E) carbonyl modifications. The total number of a given replacement is given in the intersection field. The three numbers in parentheses represent the number of replacements that increase (X _ _), do not change (_ X _) and decrease (_ _ X) the affinity. Color code: desirable substitutions (□); substitutions that decrease activity (▪); substitutions that do not influence activity (▪).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4471634&req=5

fig01: All bioisosteric replacements for 5-HT6R ligands belonging to A) halogen, B) phenyl, C) hydroxyl, D) amide, and E) carbonyl modifications. The total number of a given replacement is given in the intersection field. The three numbers in parentheses represent the number of replacements that increase (X _ _), do not change (_ X _) and decrease (_ _ X) the affinity. Color code: desirable substitutions (□); substitutions that decrease activity (▪); substitutions that do not influence activity (▪).

Mentions: The most frequent replacements for self-bioisosteres are the following: halogen replacements (nearly 50 % of all substitutions), ring modifications, and substitutions. Apparently, the hydroxyl class of substitutions was the least frequently explored within the investigated dataset. The analysis of bioisosteric substitutions for 5-HT6R ligands showed two types of substitutions that enhanced activity: 2-substituted pyridine ring substituted by other aromatic systems, especially phenyl (Table 3), and nitrile group, which are interchangeable with any halogen (Figure 1). Moreover, the introduction of sulfonamide (Table 4) and urea increases affinity towards 5-HT6R in all cases.


Bioisosteric matrices for ligands of serotonin receptors.

Warszycki D, Mordalski S, Staroń J, Bojarski AJ - ChemMedChem (2015)

All bioisosteric replacements for 5-HT6R ligands belonging to A) halogen, B) phenyl, C) hydroxyl, D) amide, and E) carbonyl modifications. The total number of a given replacement is given in the intersection field. The three numbers in parentheses represent the number of replacements that increase (X _ _), do not change (_ X _) and decrease (_ _ X) the affinity. Color code: desirable substitutions (□); substitutions that decrease activity (▪); substitutions that do not influence activity (▪).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4471634&req=5

fig01: All bioisosteric replacements for 5-HT6R ligands belonging to A) halogen, B) phenyl, C) hydroxyl, D) amide, and E) carbonyl modifications. The total number of a given replacement is given in the intersection field. The three numbers in parentheses represent the number of replacements that increase (X _ _), do not change (_ X _) and decrease (_ _ X) the affinity. Color code: desirable substitutions (□); substitutions that decrease activity (▪); substitutions that do not influence activity (▪).
Mentions: The most frequent replacements for self-bioisosteres are the following: halogen replacements (nearly 50 % of all substitutions), ring modifications, and substitutions. Apparently, the hydroxyl class of substitutions was the least frequently explored within the investigated dataset. The analysis of bioisosteric substitutions for 5-HT6R ligands showed two types of substitutions that enhanced activity: 2-substituted pyridine ring substituted by other aromatic systems, especially phenyl (Table 3), and nitrile group, which are interchangeable with any halogen (Figure 1). Moreover, the introduction of sulfonamide (Table 4) and urea increases affinity towards 5-HT6R in all cases.

Bottom Line: Analysis of a collection of over 1 million bioisosteres of compounds with measured activity towards serotonin receptors revealed that an average of 31 % of the ligands for each target are mutual bioisosteres.In addition, the collected dataset allowed the development of bioisosteric matrices-qualitative and quantitative descriptions of the biological effects of each predefined type of bioisosteric substitution, providing favored paths of modifying the compounds.The concept exemplified here for serotonin receptor ligands can likely be more broadly applied to other target classes, thus representing a useful guide for medicinal chemists designing novel ligands.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Kraków (Poland).

Show MeSH