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A Computational Analysis of Electrostatic Interactions Between Chronic Myeloid Leukemia Drugs and the Target, Bcr-Abl Kinase

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A Computational Analysis of Electrostatic Interactions Between Chronic Myeloid Leukemia Drugs and the Target, Bcr-Abl Kinase A Computational Analysis of Electrostatic Interactions Between Chronic Myeloid Leukemia Drugs and the Target, Bcr-Abl Kinase Fides G. Nyaisonga Advisor: Mala L. Radhakrishnan Submitted in Partial Fulfillment of the Prerequisite for Honors in Chemistry April 2016 © 2016 Fides Nyaisonga Acknowledgements I owe my gratitude to all those people who have made this research possible. First and foremost, my deepest gratitude is to my advisor, Professor Mala Radhakrishnan for guiding me throughout the research and writing process. Her patience and support has helped me overcome many challenges during the course of this research. I would also like to thank Professor Don Elmore for his help and insightful comments at different stages of my research. He was extremely helpful when I was learning how to do molecular dynamic simulations. Special thanks to Professor Rachel Stanley for all the personal conversations we have had concerning the thesis process and for her constructive comments during the committee meetings. I am also grateful for Professor Megan Kerr for agreeing to be on my thesis committee. Special thanks to my lab mates, Nusrat, Laura and Diane for encouraging me to finish the project and for making lab a fun environment. Also, most results described in this work were accomplished with the help and support of previous lab members, including Lucy Liu and Lucica Hiller. Thanks to all my WASA friends, especially Khalayi and Mebatsion, for providing support and friendship that I needed and for constantly checking on me. I especially thank my parents, Secilia and George, my sister, Laura and my brothers Gervas and Andrew for their unwavering love and patience throughout the four years at Wellesley. Their unconditional love and trust has enabled me to explore and pursue my passions, however many they were. I also thank my host family, Deborah and George Tall, for their love and care and for giving me a home away from home. Finally, I appreciate the support of Wellesley College for providing me with great research opportunities for the past four years. I would specially like to thank the President’s Office for the financial support for a wonderful summer research experience. Table of Contents Introduction ............................................................................................................................................. 1 Type chapter level (level 1) ................................................................................................................ 4 Type chapter level (level 2) ........................................................................................................................... 5 Type chapter title (level 3).......................................................................................................................................... 6 1 1. Introduction Chronic myeloid leukemia (CML) is a malignant blood disorder representing about 20% of adult leukemia and is characterized by the presence of the Philadephia (Ph) chromosome1. Ph refers to a shortened chromosome created by the fusion of the breakpoint cluster region (BCR) gene on chromosome 22 to the Abelson proto-oncogene (ABL) on chromosome 91-2. The ABL gene encodes a tyrosine kinase that binds to ATP and catalyzes selective phosphorylation of tyrosine hydroxyl groups to control and amplify intercellular signals3-5. The activity of a normal kinase is tightly regulated under normal conditions6. In contrast, the Bcr-Abl oncoprotein translated from the BCR-ABL fusion gene is a constantly active cytoplasmic kinase. The solved crystal structure of the Abl kinase shows a catalytic domain that consists of two lobes; the N-terminal lobe and C-terminal lobe4, 7-9. The N-lobe consists of five -sheets and one -helix while the C-lobe consists mainly of -helices (Figure 1). The ATP binding∝ site is located at the cleft between the two lobes. The activation of the kinase is controlled by the activation loop arising from the C-lobe. This loop is characterized by the Asp 381-Phe 382-Gly 383 (DFG) motif. In the kinase’s active form, the activation loop adopts a "DFG-in" conformation with Asp 381 oriented towards the binding site. This orientation allows the Asp 381 residue to coordinate the Mg2+ ions for catalysis. The inactive form of the kinase, "DFG-out", is associated with Asp 381 being rotated away from the active site and thus unable to coordinate and stabilize the catalytic ion. In addition, in this “DFG-out” conformation, the binding of ATP is also blocked by Phe 382 being positioned towards the binding cleft (Figure 1)5, 7, 10. Residue Thr 315, termed the "gatekeeper", 2 is located at the back of the ATP binding pocket, and its interaction with small molecules inhibitors determines their binding and specificity at the binding pocket11. The discovery of the Bcr-Abl oncoprotein followed by structure-based drug design have led to the development of specific inhibitory molecules that fit into and replace ATP from the binding site to inhibit the kinase's activity. In 2002, imatinib mesylate (Imatinib, Gleevec®, or STI571, Novartis Pharma AG) became the first rationally designed tyrosine kinase inhibitor (TKI) clinically approved for CML treatment8. N- Lobe ATP Binding Site Thr 5 Phe 8 Gly 8 Asp 8 C- Lobe Figure 1. The DFG-motif near the ATP binding site. The “DFG-out” conformation of Abl is characterized by a near 1800 rotation of the motif, with residue Phe 382 oriented towards the binding site, preventing ATP from binding. The "gatekeeper" residue points directly towards the ATP binding site. 3 Studies on the crystal structure of imatinib bound to the Abl kinase showed that imatinib binds specifically and stabilizes the “DFG-out” conformation shown in Figure 1, resulting in the apoptotic death of Ph-positive cells3-4, 8, 12. Imatinib binds to the ATP binding site through hydrogen bond interactions with residues Thr 315, Met 318, Glu 286, and Asp 381 as shown in Figure 2. In addition, there is a strong indication that the nitrogen atom of the piperazine group on imatinib is protonated and forms hydrogen bonds with the carbonyl oxygen atoms of Ile 360 and His 36113-16. This interaction is supported by experimental results that yielded a large equilibrium constant of the protonation of the corresponding nitrogen17. A large protonation constant makes this nitrogen the most basic site of imatinib, facilitating its role as a hydrogen bond donor17. Figure 2. (A) Imatinib bound to Abl kinase. Hydrogen bonds are formed between the N5 of imatinib and the backbone of Met 318, N13 and the side chain hydroxyl of Thr 315, N20 and the side chain of Glu 286, the carbonyl O30 and the backbone of Asp 381, and the protonated methyl piperazine with the backbone of Ile 360 and His 361. (B) Structure of imatinib. 4 Imatinib quickly became the first-line treatment of CML with 98% of early stage patients showing a complete hematologic response and an overall 5 year survival rate of 84%18. However, about 35% of patients in advanced phase CML were shown to eventually develop resistance or intolerance towards imatinib1, 19-20. Acquired resistance to imatinib is predominantly caused by a single amino acid substitution on the Abl binding site weakening or preventing the interaction of the drug to the protein1. A broad spectrum of kinase domain mutations that cause resistance have been reported21-23. Most notably is the clinically active “gatekeeper” mutation, T315I, which accounts for 15-20% of all mutation incidences24-25. The hydroxyl of the “gatekeeper” residue, Thr 315, in the wild type (WT) Abl forms a hydrogen bond to the amine linker between the pyridine and the phenyl rings of imatinib (Figure 2). The substitution of the polar Thr with a nonpolar Ile disrupts this hydrogen bond. In addition, the bulky ethyl group of Ile causes a steric clash with the phenyl ring of imatinib preventing the drug from binding to the mutant Abl while still allowing access to ATP5, 10, 26-27. 5 N- Lobe ATP Binding Site Ile 5 Phe 8 Gly 8 Asp 8 C- Lobe Figure 3. T315I mutant. Ile 315 blocks the entrance of TKIs into the binding site. In response to imatinib resistance, second generation TKIs including dasatinib (BMS- 3582, Bristol-Myers Squibb and Otsuka Pharmaceutical Co., Ltd) and nilotinib (AMN107, Novartis Pharma AG) were developed to improve the inhibitor's affinity and potency towards the mutated form of Abl. Dasatinib binds to the activated form of Abl (DFG-in conformation) and is able to inhibit most clinical mutations that affect the DFG-out state28. Nilotinib on the other hand, although structurally related to imatinib, is 30 times more potent29. However, similarly to imatinib, both dasatinib and nilotinib form a hydrogen bond with Thr 315 and are critically affected by the T315I mutation. 6 Ponatinib (AP2454, Ariad Pharmaceuticals), a third generation inhibitor, became the first TKI to have activity against the T315I mutation. X-ray crystallographic analysis of ponatinib bound to T315 Abl shows that ponatinib, like imatinib, binds to the “DFG-out” conformation, maintaining hydrogen bonding interactions with multiple residues including Phe 382 of the DFG motif 24-25, 27, 30. Figure 4. (A) The binding of ponatinib to the wild type Abl kinase. A total of six hydrogen bonds are formed between ponatinib and Abl; N1 of ponatinib with the backbone of Met 318, carbonyl O28 with the backbone of Asp 381, N29 with the side chain of Glu 286, protonated N39 with the backbones of Ile 360 and His 361. (B) Structure of ponatinib Unlike all previous TKIs, ponatinib utilizes a linear triple bond linkage between purine and methyl phenyl groups (Figure 4) to avoid steric clash with the Ile 315 residue. This, together with multiple contacts it forms with the binding site of Abl, makes ponatinib less susceptible to 7 single amino acid mutations. As a result, ponatinib showed remarkable efficacy in phase I studies whereby 98% of patients achieved and maintained complete hematologic response25. Figure 5. T315 mutation affects the topology of ATP binding region. A bulky side chain of Ile 315 interrupts hydrogen bond formation between imatinib and Abl and causes a steric clash with the phenyl ring of imatinib.
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