Page 98 - Medicinal Chemistry Self Assessment

Section 2 Whole Molecule Drug Evaluation

1.26 Sorafenib

Because protein tyrosine kinases regulate cellular proliferation, differentiation, and survival, it is no surprise that
several neoplastic disorders can be tied to altered activity of protein tyrosine kinases. Clinically relevant antineo-
plastic tyrosine kinase inhibitors interact with the active site of the enzyme via several types of binding interactions.
The adenosine triphosphate (ATP) binding domain of the tyrosine kinases contains a hydrophobic domain that
includes a significant number of isoleucine, leucine, alanine and valine residues. There are at least five binding pockets
that flank this region in which van der Waals, hydrophobic, hydrogen bonding, and electrostatic interactions occur.
Sorafenib is a tyrosine kinase inhibitor used in the treatment of advanced renal cell carcinoma, a highly vascularized
1.26 Sorafenib
tumor. The drug specifically targets vascular endothelin growth factor 2 (VEGF2) that is instrumental in the genera-

Because protein tyrosine kinases regulate
tion of new blood vessels.
C F
E

A

B D

Sorafenib
Sorafenib
1. Conduct a structural evaluation of sorafenib, focusing on the boxed functional groups, and use the infor-
1. Conduct a structural to the questions that follow.
mation in the grid to inform your answers to the questions that follow.
2. Sorafenib interacts in the local environment of the enzyme. Function
Character
Character
359
3. Nilotinib, another and Leu 298 /Val 299 Acidic, Basic, Function Interaction(s)
/Phe
in each of the respective five binding pockets.
Hydrophilic or Neutral ↑ Solubility Possible with Biological
A
Name of and/or Provide pK and/or Target at Physiological
a
Functional Group Hydrophobic When Relevant ↑ Absorption pH=7.4
A
B C D E
B
C
D
E
F

Nilotinib
A. Consider the side chains of the the five binding pockets. Assume pH=7.4.
87
B. Determine acid side chains are both at pH=7.4.

C. It has been participate in this interaction.

Methionine