Page 99 - Medicinal Chemistry Self Assessment

88 Medicinal Chemistry Self Assessment

919
2. Sorafenib interacts with Cys , Phe 1047 , and Asp 1046 via hydrogen bonding and hydrophobic interactions.
1.26 Sorafenib
Identify which functional groups could interact with the side chains of these amino acids. Assume
that Asp 1046 is unionized in the local environment of the enzyme.
Because protein tyrosine kinases regulate
Interacts with Cysteine Interacts with Aspartic Acid 1046
919
via a Hydrogen Bonding C via a Hydrogen Bonding F Interacts with Phenylalanine 1047
Interaction Interaction via a Hydrophobic Interaction
Functional E
Group Yes or No Yes or No Yes or No
A A
B
C
D B D
E
F Sorafenib

1. Conduct a structural to the questions that follow.
3. Nilotinib, another tyrosine kinase inhibitor (via Bcr-Abl) indicated for the treatment of Philadel-
2. Sorafenib interacts in the local environment of the enzyme.
phia Chromosome (Ph ) positive chronic myelogenous leukemia, also interacts with each of the five
+
285
289
286
binding pockets found within this biological target. This drug interacts with Leu /Val , Asp /Glu ,
391
299
298
359
/Val
3.
in each of the respective five binding pockets.
315 Nilotinib, another and Leu
/Phe
Thr , Met and Leu /Val /Phe in each of the respective five binding pockets.
298
299
359
318
A
B C D E
Nilotinib
Nilotinib
a. Consider the side chains of the amino acids indicated and determine which type(s) of binding
A. Consider the side chains of the the five binding pockets. Assume pH=7.4.
interactions are possible in each of the five binding pockets. Assume pH=7.4.
B. Determine acid side chains are both at pH=7.4.
285
Leu /Val 289 Asp /Glu 286 Thr 315 Met 318 Leu /Val /Phe 359
298
299
391
C. It has been participate in this interaction.
b. Determine which of the boxed functional groups (A–E) can interact with the side chains of the

amino acids found in each of the five binding pockets. Indicate the type of interaction(s) possible
in the appropriate box. None is an acceptable answer. Assume that the drug and the amino acid
side chains are both at pH=7.4.
298
285
391
Leu /Val 289 Asp /Glu 286 Thr 315 Met 318 Leu /Val /Phe 359
299
A
B
C
D
E Methionine