Page 100 - Medicinal Chemistry Self Assessment

1.26 Sorafenib

Because protein tyrosine kinases regulate
C
A
B
Sorafenib
1. Conduct a structural to the questions that follow.
2. Sorafenib interacts in the local environment of the enzyme.
299
359
298
in each of the respective five binding pockets.
/Val
3. Nilotinib, another and Leu
/Phe
A
C
B
Nilotinib D D E F E
A. Consider the side chains of the the five binding pockets. Assume pH=7.4.
1.26 Sorafenib 89
B. Determine acid side chains are both at pH=7.4.
c. It has been documented that the pyridyl nitrogen atom (functional group E) of nilotinib partici-
C. It has been participate in this interaction.
pates in a hydrogen bonding interaction with methionine. Draw a diagram that clearly shows

which atom(s) within the structure of methionine participate in this interaction.

Methionine
Methionine

4. Sorafenib enters cells via passive diffusion. Using the information in the structure evaluation grid as a
starting point, identify which functional groups contribute to the ability of this drug to enter cells via
passive diffusion.

5. Nilotinib is considered significantly more hydrophobic than sorafenib (distribution coefficient log D is
2.4 and 0.8 respectively). Provide a structural rationale for this property difference.

6. Sorafenib is marketed as a tosylate salt, a lipid-soluble organic salt. Nilotinib is marketed as a hydro-
chloride monohydrate salt, an inorganic salt. In general, what is the value of each of these types of
salts?