Sandbox Reserved 425: Difference between revisions

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OCA, Lynmarie K Thompson, Student

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 The specific binding of ponatinib can be categorized into and explained by five major chemical components, they are: (1) the template that interacts with the hinge region; (2) the A ring that occupies the hydrophobic pocket behind the gatekeeper residue; (3) the key ethynyl linker that joins the template and A ring, and that interacts with the gatekeeper residue (linker 1); (4) the A-B ring linker (linker 2); and (5) the B ring that binds to the DFG-out pocket<ref name="five" />.
-Ponatinib binds into the ATP binding pocket between the N and C lobes to induce a shift from the DFG-in to the DFG-out conformation. It covers an immense region that spans from the kinase hinge region (back of kinase) to the catalytic pocket (front of kinase). Three sites are engaged in the ATP binding cleft by ponatinib’s aromatic rings. In the first site, the imidazo[1,2b]pyridazine scaffold takes up the same space as the adenine ring of ATP and it is able to form one hydrogen bone with the backbone amide nitrogen atom of Ala553 in the <scene name='48/483882/Hinge/1'>hinge</scene> (shown in <font color='cyan'><b>cyan</b></font>) <ref name="seven" />. Both of its rings form several Van der Waals contacts with residues in the N and C lobes of the adenine binding site as well<ref name="five" />. Rigid acetylene linkage drives the rest of the drug into the back of the ATP binding pocket. In the second site, the methylphenyl group displaces the side chain of the catalytic Lys503 and its aromatic ring binds to the hydrophobic pocket that is formed by Val550, the <scene name='48/483882/Gatekeeper/1'>gatekeeper</scene> residue (shown in <font color='yellow'><b>yellow</b></font>), and Met524<ref name="seven" />. Val550 is stabilized by the benzimide group<ref name="six">PMID: 25478866</ref>. This displacement allows Glu520 in the αC helix to hydrogen bond with the amide linkage between the aromatic rings in ponatinib. In the third site, Phe631 of DFG is expelled out of the cleft by ponatinib’s 3-trifluoromethylphenyl moiety, which takes the place of Phe631. Phe631’s new position enables it to make hydrophobic contact with the drug’s scaffold and acetylene linker. Also, Asp630 of DFG becomes available for hydrogen bonding with the amide linkage between the aromatic rings in ponatinib. This also puts the piperazine ring in the position to engage in hydrogen bonding with the catalytic loop. This is shift forms the DFG-out conformation<ref name="seven" />.
+Ponatinib binds into the ATP binding pocket between the N and C lobes to induce a shift from the DFG-in to the DFG-out conformation. It covers an immense region that spans from the kinase hinge region (back of kinase) to the catalytic pocket (front of kinase). Three sites are engaged in the ATP binding cleft by ponatinib’s aromatic rings. In the first site, the imidazo[1,2b]pyridazine scaffold takes up the same space as the adenine ring of ATP and it is able to form one hydrogen bond with the backbone amide nitrogen atom of Ala553 in the <scene name='48/483882/Hinge/1'>hinge</scene> (shown in <font color='cyan'><b>cyan</b></font>) <ref name="seven" />. Both of its rings form several Van der Waals contacts with residues in the N and C lobes of the adenine binding site as well<ref name="five" />. Rigid acetylene linkage drives the rest of the drug into the back of the ATP binding pocket. In the second site, the methylphenyl group displaces the side chain of the catalytic Lys503 and its aromatic ring binds to the hydrophobic pocket that is formed by Val550, the <scene name='48/483882/Gatekeeper/1'>gatekeeper</scene> residue (shown in <font color='yellow'><b>yellow</b></font>), and Met524<ref name="seven" />. Val550 is stabilized by the benzimide group<ref name="six">PMID: 25478866</ref>. This displacement allows Glu520 in the αC helix to hydrogen bond with the amide linkage between the aromatic rings in ponatinib. In the third site, Phe631 of DFG is expelled out of the cleft by ponatinib’s 3-trifluoromethylphenyl moiety, which takes the place of Phe631. Phe631’s new position enables it to make hydrophobic contact with the drug’s scaffold and acetylene linker. Also, Asp630 of DFG becomes available for hydrogen bonding with the amide linkage between the aromatic rings in ponatinib. This also puts the piperazine ring in the position to engage in hydrogen bonding with the catalytic loop. This is shift forms the DFG-out conformation<ref name="seven" />.
 Other inhibitors are not as potent as ponatinib against FGFR kinases because they are unable to penetrate far enough to access the third site and cannot assume the DFG-out conformation<ref name="seven" />.