Abstract
Extremely high affinity and selectivity are two of the most sought-after properties of drug molecules. Selectivity has been difficult to achieve, especially for targets that belong to large families of structurally and functionally related proteins. There are essentially two ways by which selectivity can be improved during lead optimization: a chemical modification of the lead compound that improves the affinity towards the target to a higher extent than to off-target molecules; and a chemical modification that lowers the affinity of the lead compound towards off-target molecules. Maximal selectivity is achieved when both mechanisms can be combined synergistically. As we discuss here, analysis of several protease inhibitors that vary in a single functionality indicates that nonpolar functionalities preferentially follow the first mechanism, whereas polar functionalities follow the second, and that those features are imprinted in their thermodynamic signatures.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 985-990 |
| Number of pages | 6 |
| Journal | Drug Discovery Today |
| Volume | 16 |
| Issue number | 21-22 |
| DOIs | |
| State | Published - Nov 2011 |
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ASJC Scopus subject areas
- Drug Discovery
- Pharmacology
Cite this
Finding a better path to drug selectivity. / Kawasaki, Yuko; Freire, Ernesto I.
In: Drug Discovery Today, Vol. 16, No. 21-22, 11.2011, p. 985-990.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Finding a better path to drug selectivity
AU - Kawasaki, Yuko
AU - Freire, Ernesto I
PY - 2011/11
Y1 - 2011/11
N2 - Extremely high affinity and selectivity are two of the most sought-after properties of drug molecules. Selectivity has been difficult to achieve, especially for targets that belong to large families of structurally and functionally related proteins. There are essentially two ways by which selectivity can be improved during lead optimization: a chemical modification of the lead compound that improves the affinity towards the target to a higher extent than to off-target molecules; and a chemical modification that lowers the affinity of the lead compound towards off-target molecules. Maximal selectivity is achieved when both mechanisms can be combined synergistically. As we discuss here, analysis of several protease inhibitors that vary in a single functionality indicates that nonpolar functionalities preferentially follow the first mechanism, whereas polar functionalities follow the second, and that those features are imprinted in their thermodynamic signatures.
AB - Extremely high affinity and selectivity are two of the most sought-after properties of drug molecules. Selectivity has been difficult to achieve, especially for targets that belong to large families of structurally and functionally related proteins. There are essentially two ways by which selectivity can be improved during lead optimization: a chemical modification of the lead compound that improves the affinity towards the target to a higher extent than to off-target molecules; and a chemical modification that lowers the affinity of the lead compound towards off-target molecules. Maximal selectivity is achieved when both mechanisms can be combined synergistically. As we discuss here, analysis of several protease inhibitors that vary in a single functionality indicates that nonpolar functionalities preferentially follow the first mechanism, whereas polar functionalities follow the second, and that those features are imprinted in their thermodynamic signatures.
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UR - http://www.scopus.com/inward/citedby.url?scp=80255126234&partnerID=8YFLogxK
U2 - 10.1016/j.drudis.2011.07.010
DO - 10.1016/j.drudis.2011.07.010
M3 - Article
C2 - 21839183
AN - SCOPUS:80255126234
VL - 16
SP - 985
EP - 990
JO - Drug Discovery Today
JF - Drug Discovery Today
SN - 1359-6446
IS - 21-22
ER -