Three-Dimensional Visualization of Kinase Inhibitors as

Activity Cite This: J. Chem. Educ. XXXX, XXX, XXX−XXX

pubs.acs.org/jchemeduc

Three-Dimensional Visualization of Kinase Inhibitors as Therapeutically Relevant Examples To Reinforce Types of Enzyme Inhibitors Sonali Kurup*,† and Prashant Sakharkar College of Pharmacy, Roosevelt University, Schaumburg, Illinois 60173, United States

Downloaded via UNIV OF LOUISIANA AT LAFAYETTE on January 11, 2019 at 13:27:03 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

S Supporting Information *

ABSTRACT: An activity is described that incorporates three-dimensional visualization of therapeutic agents to reinforce lecture concepts of enzyme structure and inhibition and further relate these concepts to applications for drug action. Investigational and FDA-approved kinase inhibitors developed as anticancer agents were utilized as therapeutically relevant examples of enzyme inhibitors to illustrate enzyme−inhibitor interactions and correlate mechanisms of enzyme inhibition to drug action. Student cohorts were required to answer a series of questions while visualizing the three-dimensional enzyme active site and inhibitor-bound enzyme complexes. Student impressions of the activity based on a survey were positive. Student learning for concepts covered as part of the activity was evaluated using performance on examination questions. KEYWORDS: Molecular Modeling, Enzymes, Biochemistry, Medicinal Chemistry, Computer-Based Learning, Inquiry-Based/Discovery Learning, Hands-On Learning/Manipulatives, Upper-Division Undergraduate, Graduate Education/Research

■

INTRODUCTION Biochemistry is a core course taught as part of the undergraduate science curricula and professional programs including medicine and pharmacy. Enzyme inhibition is one of the topics covered as part of the course that presents several abstract concepts that are difficult for students to grasp. Laboratory modules, problem-based learning, and an early exposure to clinically relevant examples for foundational concepts have demonstrated positive outcomes for student engagement and provided context for the information learned.1−8 Molecular visualization of protein structures in three dimensions is an alternate successful pedagogical approach in advanced application-based courses such as medicinal chemistry, molecular biology, and pharmacology in the health science curricula.9−18 A variety of three-dimensional visualization software has been utilized including commercial software and free molecular modeling software.11−18 The activity described here utilizes molecular modeling as a tool to demonstrate enzyme−ligand interactions similar to other activities using three-dimensional visualization. It is different from the literature reports on the basis of its illustration of multiple classes of enzyme inhibitors for a common enzyme pocket. The enzyme inhibitors used as examples are FDA-approved drugs or potential drug candidates that reiterate the relevance of the mechanism of enzyme inhibition on drug action. The activity is novel in regards to further demonstrating the clinical relevance of the varied types of enzyme inhibitors by relating the mechanism of enzyme inhibition such as reversible, irreversible, or allosteric to concepts of potency, selectivity, and resistance that are important considerations for clinical use. The kinases, Abelson leukemia (ABL) kinase and epidermal growth factor receptor (EGFR) kinase, are used as example © XXXX American Chemical Society and Division of Chemical Education, Inc.

kinases for the activity. Over 50 kinase inhibitors have been approved by the US Food and Drug Administration for cancer.19 Kinase inhibitors are specifically classified on the basis of interactions within the kinase where Type I inhibitors bind exclusively to the active site, Type II inhibitors bind to the active site and extend into a deep hydrophobic pocket outside the active site, and Type III and IV inhibitors do not bind at the active site and are classified as allosteric inhibitors. Type V inhibitors are bivalent and bind to two different sites of the kinase. Type VI inhibitors are irreversible and interact covalently with kinases.20,21 Type I−VI kinase inhibitors vary in their therapeutic application on the basis of selectivity and resistance profiles and provide valuable examples to demonstrate the therapeutic relevance of varied mechanisms of inhibition. The activity thus was anticipated to help a transition from foundational science to therapeutic application. The molecular modeling software, Molecular Operating Environment (MOE),22 was used for the three-dimensional visualization of the enzyme active site and kinase inhibitors. A complementary teaching license for use on multiple computers is available for faculty who adopt this for their research. The choice of MOE is based on the availability of a complementary teaching license and additional features such as ligand interaction maps, ease of use, and clear graphics that improve the overall quality of instruction compared to that of the freeware. Received: May 30, 2018 Revised: December 5, 2018

A

DOI: 10.1021/acs.jchemed.8b00403 J. Chem. Educ. XXXX, XXX, XXX−XXX

Journal of Chemical Education

Activity

Figure 1. Substrates and transition state for the ABL kinase-catalyzed reaction.

Figure 2. Active site of ABL kinase (modified and adopted from 2G1T). The structure of ATP is shown in orange, and the peptidic substrate is shown in gray. The structure includes nitrogen in blue, oxygen in red, hydrogen in white, magnesium in brown, and phosphorus in pink. Interactions between ATP and the active site are shown as dashed lines.

■

THE ACTIVITY

Students were assigned alphabetically and worked in groups of 3 to complete the assignment during designated lab times. The question-driven, hands-on assignment format was expected to encourage review and learning. The pedagogical goals of the activity were the following: (1) identification of interactions within the active site, (2) identification of enzyme inhibitors based on the site of binding and types of interactions within the kinase enzyme, and (3) therapeutic application of enzyme inhibition. The activity was piloted in 2011 and has been implemented every year since then. The activity received IRB

Enzyme structure, kinetics, and inhibition were taught in a lecture format in an introductory biochemistry course. The concepts relating to the enzyme active site, enzyme−ligand interactions, and types of enzyme inhibitors were further reinforced using the activity described. Students were required to visualize enzyme structures and inhibitors using MOE and answer specific questions relating to enzyme inhibition. Four 2 h long modeling lab sessions were offered to accommodate a class of 71 students and included 18 students per session. B



Activity

Figure 3. ABL kinase inhibitors 4−7 and EGFR kinase inhibitors 8−9.

Table 1. Activity Assignment Questions by Their Corresponding Pedagogical Goals Ligand

Assignment Question

Pedagogical Goal 1: Identification of Interactions within the Active Site Substrates: Question 1: List at least five residues that ATP interacts with. ATP and 12mer peptide Question 2: Identify at least one type of bond formed. List the residues and functional groups on ATP involved in the bond. Pedagogical Goal 2: Identification of Enzyme Inhibitors Based on the Site of Binding and Types of Interactions within the Kinase Enzyme ATPγS (4) Question 3: List at least five residues that interact with ATPγS. Do any of these residues overlap with residues also interacting with ATP? Question 4: What type of inhibitor is ATPγS? Imatinib (5) Question 5: Imatinib is an approved ABL inhibitor used in chronic myeloid leukemia. Imatinib binds in the same pocket as ATPγS. What type of inhibitor is imatinib? GNF-2 (6) Question 6: (a) Identify at least two residues that interact with GNF-2. Are these the same residues that interact with imatinib? (b) What type of inhibitor is GNF-2? Compound 7 Question 7: (a) List at least five residues that interact with 7. Identify the types of bonds formed. (b) What type of inhibitor is 7? Compound 9 Question 8: (a) List at least five residues that interact with compound 9. (b) Identify the types of bonds formed. (c) What type of inhibitor is compound 9? Compounds Question 9: Identify any additional studies you would like to conduct to confirm your results. 4−9 Pedagogical Goal 3: Therapeutic Application of Concepts from Enzyme Inhibition Imatinib (5) Question 5b: ATPγS is not approved in the treatment of chronic myeloid leukemia. Compare the structures of ATPγS and imatinib to ATP. and ATPγS (4) Explain why ATPγS is not approved for therapy. Base your answer on the two most important attributes of an inhibitor. Erlotinib (8) Discussion for a comparison of the clinical applications of reversible and irreversible EGFR inhibitors. and 9

onto the laboratory computers.24−27 Features of MOE utilized by students for visualization of the enzyme−ligand complexes included rotation of structures and bonds, varying the structural display and generation of ligand interaction plots. For the first part of the activity, the reaction catalyzed by ABL kinase, the two substrates ATP, 1, and a 12-mer peptide, 2, and the transition state, 3 (Figure 1), were provided to students.

approval for collection and reporting of student survey data in 2015. For wider applicability, a description of the activity using Ligand Explorer, molecular modeling software available freely through the RCSB Protein Data Bank, is included on page S8 of the Supporting Information.23,24 Crystal structures for three-dimensional visualization were downloaded from the RCSB Protein Data Bank and preloaded C



Activity

Figure 4. Interactions for ATPγS 4 within ABL kinase are shown (modified and adopted from PDB ID: 2G1T). The structure for ATPγS includes carbons in white, nitrogen in blue, oxygen in red, sulfur in yellow, and phosphorus in pink. The interactions between ATPγS and the active site are shown as dashed lines.

replaces cysteine with serine in the EGFR kinase has developed in recent years.34 Unlike the cysteine residue, the serine does not form a covalent bond to the inhibitor.

The reported crystal structure of the bisubstrate ABL kinase inhibitor (PDB: 2G1T) incorporated ATPγS as the ATPcompetitive fragment linked through an acetyl moiety to a 4aminophenylalanine-containing polypeptide as the substrate peptide-competitive fragment.24 The crystal structure was modified by the instructor to highlight the active site, ATP as substrate 1 and the 12-mer peptide as substrate 2 (Figure 2). The crystal structures for varied ABL kinase inhibitors including ATPγS (4), imatinib (5), GNF-2 (6) and 7, and EGFR kinase inhibitors 8 (erlotinib) and 9 were loaded on student computers (Figure 3).24−29 Students visualized the structures of enzyme−inhibitor complexes and answered the questions described in Table 1 in order to identify interactions within the enzyme pocket and to identify the mechanism of inhibition for compounds 4−7 (Figures 3−6) using the following choices: (A) substrate-competitive inhibitor, (B) transition state analogue inhibitor, (C) noncompetitive inhibitor, (D) uncompetitive inhibitor, and (E) irreversible inhibitor. A discussion followed the assignment to further build on therapeutically relevant concepts. Imatinib was compared to ATPγS to reinforce potency and selectivity. ATP is a common substrate for all kinases. ATPγS, being ATP-like, binds to ABL kinase and all other kinases resulting in off-target binding and adverse effects. Imatinib is less ATP-like in structure and is a Type II inhibitor that explores an additional hydrophobic pocket within ABL kinase and provides greater potency and selectivity.30,31 Resistance was discussed using erlotinib and 9 as examples. Both inhibitors were ATP-competitive EGFR kinase inhibitors. Erlotinib is reversible with a key interaction to a threonine 279 residue. Resistance has been reported for erlotinib due to a mutation of threonine 279 to a larger methionine.32,33 A covalent bond with a cysteine residue in the EGFR kinase pocket is observed for 9 instead of a reversible interaction with Thr279, allowing it to be effective in Thr279Met mutant EGFR kinase (Figure 7). A new resistant mutation that

■

RESULTS AND DISCUSSION Students met each of the pedagogical goals by answering questions on the assignment relating to each goal as shown in Table 1. Explanations for each response are included as Instructor Notes in the Supporting Information. Incorrect answers included identifying an incorrect mechanism of inhibition, incorrect pocket interactions, or unclear justifications for answers. Students who responded incorrectly to questions were asked to review content and amend their responses. The instructor reviewed pertinent lecture concepts with students where necessary. This interaction between the instructor and student cohorts helped the instructor gauge student understanding and required students to think more deeply about the concept. All students received a 100% score on the assignment. For future offerings, students will also take an individual quiz during the activity to allow for an individual assessment. Student learning was estimated from performance on examination questions. The examination included 99 questions of which 46 focused on enzyme structure, kinetics, and inhibition. Of the 46 questions, 10 were related to concepts covered as part of the activity. These 10 questions included 2 questions in the multiple-answer format and 8 questions in the multiple-choice format that had only one correct answer. The multiple-answer questions were excluded in mean score calculations. The mean score on the examination was 71.6 ± 19.2 (median 73.1). The mean score for examination questions on enzyme concepts that were reinforced as part of the activity was 76.7 ± 22.9 (median 86.6). The mean score on examination questions that focused on enzyme concepts that were not reinforced as part of the activity was 66.8 ± 19 (median 70.1). This difference in the mean scores was D



Activity

Figure 5. Interactions for imatinib (white) and GNF-2, 6 (green), within ABL kinase (PDB ID: 3K5V) are shown. The structure includes nitrogen in blue and oxygen in red.

the enzyme−inhibitor interactions in three dimensions and working in a group. This is consistent with literature reports identifying team-based learning and molecular visualization as effective pedagogical approaches.35,36 There were 37 comments received in response to what students liked the least about the assignment. A few students commented on the complexity of the software and needed some more time for hands-on practice. The students were provided instructions for the use of the software; however, this was the first exposure of many students to molecular modeling software, and it could be daunting to novice users. A practice session for students to familiarize themselves with the software prior to completing the activity might have been beneficial. This activity has certain limitations. The assignment did not include an example of an uncompetitive inhibitor leading to several questions from students on this particular type of enzyme inhibition, requiring an additional discussion when students turned in their assignments. The price of the molecular modeling software, MOE, could be a limiting factor. With slight modifications, the activity could be adapted to

statistically significant (p < 0.005), suggesting that the activity contributed toward improving student learning for enzyme concepts covered as part of the assignment. Students performed poorly on multiple-answer questions on the examination. For the first multiple-answer question, 75% of the students identified at least one of the correct answers, while only 25% identified both correct responses. For the second multiple-answer question, 95% of the students identified at least one of the correct answers, while only 49% identified both correct responses. To assess student perceptions of the assignment, students completed a short survey questionnaire that included 5 items on a 4-point Likert scale (strongly agree = 1, agree = 2, disagree = 3, and strongly disagree = 4) and 2 open-ended questions (Table 2). The survey was administered in a paper format, and results were assessed using SPSS ver. 21. Results showed that the activity was well-received by students. In response to the open-ended question on what students liked the most about the assignment (item 6), 53 responses were received, and students indicated that they enjoyed visualizing E



Activity

Figure 6. Interactions for a bisubstrate inhibitor, 7, within ABL kinase (PDB ID: 2G1T) are shown. The structure includes carbons in white, nitrogen in blue, oxygen in red, sulfur in yellow, and phosphorus in pink. Interactions between 7 and the active site are shown as dashed lines.

Figure 7. Interactions for an irreversible kinase inhibitor, 9, within EGFR kinase (PDB ID: 2QQ7). The structure includes carbons in white, nitrogen in blue, oxygen in red, sulfur in yellow, and bromine in brown. A covalent interaction between 9 and Cys345 of EGFR kinase is observed.

F



Activity

Table 2. Comparative Student Responses Indicating Their Perceptions of the Assigned Activity “Strongly Agree” and “Agree”, Combineda

Scoresa

Survey Statements for Student Response

N

%

Mean

SD

(1) The modeling lab assignment helped illustrate concepts of inhibitor classification, and enzyme−substrate and enzyme−inhibitor interactions. (2) The guidance received from the instructor during the modeling lab assignment was sufficient to complete the assignment. (3) The modeling lab assignment improved my overall understanding of concepts of inhibitor classification, and enzyme−substrate and enzyme−inhibitor interactions. (4) This assignment was beneficial and should be continued in the future. (5) 3D visualization of the enzyme active site and enzyme−substrate and enzyme−inhibitor complexes using the MOE software improved my overall understanding of the topics.

71

92.0

1.70

0.90

71 70

92.0 84.0

1.48 1.90

0.88 1.06

70 70

87.1 85.7

1.81 1.76

1.01 0.81

a

Students used this 4-point Likert scale: 1, Strongly Agree; 2, Agree; 3, Disagree; and 4, Strongly Disagree.

■

ACKNOWLEDGMENTS The authors thank the Protein Data Bank for crystallographic data and Molecular Operating Environment (www.chemcomp. com) for free teaching licenses made available for the activity. The authors also acknowledge Lawrence Potempa for his input during the early development of this activity and Robert Senones for his assistance during the implementation of this activity.

other software that are freely available through the Protein Data Bank.18,23 The activity has been described using Ligand Explorer, as part of the Supporting Information. The performance on the examination for activity-related topics was lower for multiple-answer questions compared to singleanswer questions, perhaps suggesting that some clarification and guidance may still be needed to help students rationalize when there is more than one correct answer.

■

■

CONCLUSION The activity incorporating ABL and EGFR kinase inhibitors allowed the visualization and identification of different types of enzyme inhibitors and demonstrated clinical relevance for the mechanism of inhibition. The activity utilized MOE as the visualization software but could also be implemented with alternate modeling software. The format of the activity allowed an opportunity for a structured review of lecture concepts with immediate feedback and guidance from the instructor. The activity described here, if introduced early in the professional curricula of pharmacy, nursing, or medical programs, could help bridge the gap between conceptual knowledge and clinical application for students.

■

(1) Barton, J. S. A Comprehensive Enzyme Kinetic Exercise for Biochemistry. J. Chem. Educ. 2011, 88, 1336−1339. (2) Ault, A. Understanding Enzyme Inhibition. J. Chem. Educ. 2002, 79, 311. (3) Bearne, S. L. Illustrating Enzyme Inhibition Using Gibbs Energy Profiles. J. Chem. Educ. 2012, 89, 732−737. (4) Ramirez-Paz, J.; Ortiz-Andrade, B. M.; Griebenow, K.; DíazVázquez, L. Show Yourself, Asparaginase: An Enzymatic Reaction Explained through a Hands-On Interactive Activity. J. Chem. Educ. 2017, 94, 722−725. (5) Guerra, N. P. Enzyme Kinetics Experiment with the Multienzyme Complex Viscozyme L and Two Substrates for the Accurate Determination of Michaelian Parameters. J. Chem. Educ. 2017, 94, 795−799. (6) Brown, C. E.; Henry, M. L. M.; Barbera, J.; Hyslop, R. M. A Bridge between Two Cultures: Uncovering the Chemistry Concepts Relevant to the Nursing Clinical Practice. J. Chem. Educ. 2012, 89, 1114−1121. (7) Park, B.; Holman, R. W.; Slade, T.; Murdock, M.; Rodnick, K. J.; Swislocki, A. L. M. A Biochemistry Question-Guided Derivation of a Potential Mechanism for HbA1c Formation in Diabetes Mellitus Leading to a Data-Driven Clinical Diagnosis. J. Chem. Educ. 2016, 93, 795−797. (8) Martin, C.; Dewprashad, B.; Kosky, C.; Vaz, G. S. Using Clinical Cases To Teach General Chemistry. J. Chem. Educ. 2004, 81, 1471. (9) White, B.; Kim, S.; Sherman, K.; Weber, N. Evaluation of Molecular Visualization Software for Teaching Protein Structure. Biochem. Mol. Biol. Educ. 2002, 30, 130−136. (10) Abualia, M.; Schroeder, L.; Garcia, M.; Daubenmire, P. L.; Wink, D. J.; Clark, G. A. Connecting Protein Structure to Intermolecular Interactions: A Computer Modeling Laboratory. J. Chem. Educ. 2016, 93, 1353−1363. (11) Carvalho, I.; Borges, A. D. L.; Bernardes, L. S. C. Medicinal chemistry and molecular modeling: An integration to teach drug structure-activity relationship and the molecular basis of drug action. J. Chem. Educ. 2005, 82, 588−596. (12) Roy, U.; Luck, L. A. Molecular modeling of estrogen receptor using molecular operating environment. Biochem. Mol. Biol. Educ. 2007, 35, 238−243.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available on the ACS Publications website at DOI: 10.1021/acs.jchemed.8b00403. Assignment using MOE and assignment using Ligand Explorer, instructor notes, and examination questions (PDF, DOCX)

■

REFERENCES

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Sonali Kurup: 0000-0003-4722-7862 Present Address †

College of Pharmacy, Ferris State University, 220 Ferris Drive, Big Rapids, MI 49546, United States. Notes

The authors declare no competing financial interest. G



Activity

(13) Richardson, A.; Bracegirdle, L.; McLachlan, S. I. H.; Chapman, S. R. Use of a Three-Dimensional Virtual Environment to Teach Drug-Receptor Interactions. Am. J. Pharm. Educ. 2013, 77 (1), No. 11. (14) Hayes, J. M. An Integrated Visualization and Basic Molecular Modeling Laboratory for First-Year Undergraduate Medicinal Chemistry. J. Chem. Educ. 2014, 91, 919−923. (15) Satyanarayanajois, S. D. Active-learning exercises to teach drugreceptor interactions in a medicinal chemistry course. Am. J. Pharm. Educ. 2010, 74 (8), No. 147. (16) Rodrigues, R. P.; Andrade, S. F.; Mantoani, S. P.; Eifler-Lima, V. L.; Silva, V. B.; Kawano, D. F. Using free computational resources to illustrate the drug design process in an undergraduate medicinal chemistry course. J. Chem. Educ. 2015, 92, 827−835. (17) Tavares, M. T.; Primi, M. C.; Silva, N. A. T. F.; Carvalho, C. F.; Cunha, M. R.; Parise-Filho, R. Using an in silico approach to teach 3D pharmacodynamics of the drug−target interaction process focusing on selective COX2 inhibition by Celecoxib. J. Chem. Educ. 2017, 94, 380−387. (18) Craig, P. A.; Michel, L. V.; Bateman, R. C. A Survey of Educational Uses of Molecular Visualization Freeware. Biochem. Mol. Biol. Educ. 2013, 41, 193−205. (19) Turkson, J. Cancer Drug Discovery and Anticancer Drug Development. In The Molecular Basis of Human Cancer; Coleman, W., Tsongalis, G., Eds.; Humana Press: New York, 2017; pp 695−707. DOI: 10.1007/978-1-59745-458-2_36 (accessed December 2018). (20) Li, B.; Liu, Y.; Uno, T.; Gray, N. Creating chemical diversity to target protein kinases. Comb. Chem. High Throughput Screening 2004, 7, 453−472. (21) Roskoski, R., Jr. Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes. Pharmacol. Res. 2016, 103, 26−48. (22) Molecular Operating Environment (MOE 2013.08); Chemical Computing Group ULC: Montreal, Canada, 2018. https://www. chemcomp.com/MOE-Molecular_Operating_Environment.htm (accessed December 2018). (23) RCSB Protein DataBank. http://www.rcsb.org (accessed December 2018). (24) Berman, H. M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T. N.; Weissig, H.; Shindyalov, I. N.; Bourne, P. E. The Protein Data Bank. Nucleic Acids Res. 2000, 28, 235−242. (25) Levinson, N.; Kuchment, O.; Shen, K.; Young, M. A.; Koldobskiy, M.; Karplus, M.; Cole, P. A.; Kuriyan, J. A SRC-like inactive conformation in the ABL tyrosine kinase domain. PLoS Biol. 2006, 4 (5), e144. (26) Zhang, J.; Adrián, F. J.; Jahnke, W.; Cowan-Jacob, S. W.; Li, A. G.; Iacob, R. E.; Sim, T.; Powers, J.; Dierks, C.; Sun, F.; Guo, G. R.; Ding, Q.; Okram, B.; Choi, Y.; Wojciechowski, A.; Deng, X.; Liu, G.; Fendrich, G.; Strauss, A.; Vajpai, N.; Grzesiek, S.; Tuntland, T.; Liu, Y.; Bursulaya, B.; Azam, M.; Manley, P. W.; Engen, J. R.; Daley, G. Q.; Warmuth, M.; Gray, N. S. Targeting wild-type and T315I Bcr-Abl by combining allosteric with ATP-site inhibitors. Nature 2010, 463, 501−506. (27) Michalczyk, A.; Klüter, S.; Rode, H. B.; Simard, J. R.; Grütter, C.; Rabiller, M.; Rauh, D. Structural insights into how irreversible inhibitors can overcome drug resistance in EGFR. Bioorg. Med. Chem. 2008, 16, 3482−3488. (28) Wang, Z.; Cole, P. A. Catalytic mechanisms and regulation of protein kinases. Methods Enzymol. 2014, 548, 1−21. (29) Stamos, J.; Sliwkowski, M. X.; Eigenbrot, C. Epidermal Growth Factor Receptor tyrosine kinase domain with 4-anilinoquinazoline inhibitor erlotinib. J. Biol. Chem. 2002, 277, 46265−46272. (30) Blair, J. A.; Rauh, D.; Kung, C.; Yun, C. H.; Fan, Q. W.; Rode, H.; Zhang, C.; Eck, M. J.; Weiss, W. A.; Shokat, K. M. StructureGuided Development of Affinity Probes for Tyrosine Kinases Using Chemical Genetics. Nat. Chem. Biol. 2007, 3, 229−238. (31) Liao, J. J. Molecular Recognition of Protein Kinase Binding Pockets for Design of Potent and Selective Kinase Inhibitors. J. Med. Chem. 2007, 50, 409−424.

(32) Lin, Y. L.; Meng, Y.; Jiang, W.; Roux, B. Explaining why Gleevec is a specific and potent inhibitor of Abl kinase. Proc. Natl. Acad. Sci. U. S. A. 2013, 110, 1664−1669. (33) Chong, C. R.; Janne, P. A. The quest to overcome resistance to EGFR-targeted therapies in cancer. Nat. Med. 2013, 19, 1389−1400. (34) Ercan, D.; Choi, H. G.; Yun, C. H.; Capelletti, M.; Xie, T.; Eck, M. J.; Gray, N. S.; Janne, P. A. EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors. Clin. Cancer Res. 2015, 21, 3913−3923. (35) Evans, H. G.; Heyl, D. L.; Liggit, P. Team-Based Learning, Faculty Research, and Grant Writing Bring Significant Learning Experiences to an Undergraduate Biochemistry Laboratory Course. J. Chem. Educ. 2016, 93, 1027−1033. (36) Kolluru, S.; Roesch, D. M.; de la Fuente, A. A. A multiinstructor, team-based, active-learning exercise to integrate basic and clinical sciences content. Am. J. Pharm. Educ. 2012, 76 (2), No. 33.

H


Three-Dimensional Visualization of Kinase Inhibitors as

Recommend Documents