Resources for an Investigative and Sustainable Undergraduate

Oct 22, 2012 - Department of Biochemistry, Alma College, Alma, Michigan 48801, United States. ABSTRACT: Medicinal chemistry, a field typically left to...
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Communication pubs.acs.org/jchemeduc

Resources for an Investigative and Sustainable Undergraduate Medicinal Chemistry Research Program Jeffrey A. Turk*,† and Joe D. Beckmann‡ †

Department of Chemistry and ‡Department of Biochemistry, Alma College, Alma, Michigan 48801, United States ABSTRACT: Medicinal chemistry, a field typically left to the graduate and commercial realm, can be an effective pedagogical tool at an undergraduate institution. The drug-discovery process can be used as a tool to provide a broad range of research experiences that includes the design, synthesis, and testing of novel small molecules as potentially new therapeutic agents. Herein we discuss our scientific and pedagogical efforts and detail some of the available resources that faculty working at primarily undergraduate colleges may find useful in their exploration of a medicinal chemistry-related research program.

KEYWORDS: First-Year Undergraduate/General, Second-Year Undergraduate, Upper-Division Undergraduate, Biochemistry, Organic Chemistry, Computer-Based Learning, Inquiry-Based/Discovery Learning, Drugs/Pharmaceuticals



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any undergraduate students will assume positions in the pharmaceutical industry after they graduate; however, few students are exposed to drug discovery or medicinal chemistry as a part of their undergraduate education. Medicinal chemistry provides opportunities for interdisciplinary and investigative learning that are attractive and effective within an undergraduate curriculum. Early experiences with drug design, synthesis, and testing augments student interest and awareness of how traditional pedagogies are applied and transferred to pharmaceutical and biotechnological sectors. Computational and material resources are available to implement and sustain such a program at undergraduate institutions. An undergraduate medicinal chemistry research program is described, both as independent study and in the standard curriculum.



STUDENT RESEARCH

At our college, student participation in research is highly recommended and students are encouraged to seek research projects and to participate by enrolling in independent study courses. Most students elect 1−2 credits per term, which translates to 4−8 h of research activity per week. Independent study during the summer is also available with stipends awarded by the department(s), competitive college grants, and faculty external grants. Students can enroll in independent study courses at any point in their academic career; however, most that have joined our group did so in their second year and spend, on average, two to three academic semesters and one summer in our research laboratories. © XXXX American Chemical Society and Division of Chemical Education, Inc.

MEDICINAL CHEMISTRY RESEARCH PROGRAM

With modest knowledge of enzyme structure and function, students are able to identify relevant biochemical targets. Molecular visualization programs are plentiful, and (Mac)PyMOL was selected.1 This program provides sufficiently robust display options to initiate structure-based ligand design. For example, Protein Data Bank files of influenza virus neuraminidase (N1), which contains an obvious but complex substrate-binding domain, were used. Principles of ligand binding may be learned at this point. Students equipped with a basic understanding of organic chemistry, molecular properties, and molecular forces may then attempt to design ligands to match the selected binding site. It is helpful to provide something known, such as the antiviral drug osteltamivir (marketed as Tamiflu) binding to N1, to initiate their constructions. Students then test their compounds in silico. AutoDock is a suite of automated docking tools and is available free of charge from The Scripps Research Institute.2,3 Students first generate a rectangular grid surrounding the active site of the enzyme. After calculating atomic affinity at each point within the grid, AutoDock then predicts low-energy (high-affinity) ligand− enzyme coordination structures (Figure 1). Autodock can also conduct virtual high-throughput screening. ZINC4 is a free database of over 8 million commercially available compounds for virtual screening that provides an excellent source for identifying potential leads.5 The next challenge is actual ligand synthesis. This phase requires advanced synthetic, analytical, and purification

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enhancement award) grant is available to institutions that have not been major recipients of NIH research grant funds.



IMPLEMENTING RESEARCH INTO THE STANDARD CURRICULUM Exposure to open-ended investigations within the classroom helps develop a research culture among the students. Aspects of the research described above have been incorporated into a medicinal chemistry course by requiring students (i) to model inhibitor−neuraminidase complexes and identify key interactions; (ii) to validate proposed inhibitors by studying electronic characteristics, identify pharmacophores, comment on bioavailability, and so forth; and (iii) to propose their own unique inhibitor. Although the medicinal chemistry course does not have an accompanying laboratory, an advanced organic chemistry course offers an intensive laboratory experience. This course provides training so students can independently operate NMR, HPLC, IR, and other instruments that are vital to a research program. In addition to learning advanced synthetic techniques, some laboratory experiments charge students with creating small molecules that are potential enzyme inhibitors. Methods for assaying enzymes and small-molecule inhibitor candidates are also included in the advanced biochemistry course.



Figure 1. (A) Active site identified prior to generating atomic affinity grids using Autodock 4.0. (B) PyMOL rendering of small molecule docked into active site.

IMPACT OF THE PROGRAMS

During more than two decades of offering the medicinal chemistry course, Alma College has enrolled approximately 20 students annually. Although the course has no lab, it provides a gateway for student research involvement and some students continue on in medical chemistry to do research. In the past four years, 12 students have participated in the independent research program described here, and 11 students have traveled to two local and two national ACS meetings for poster presentations. Presentation of results at local, regional, and national conferences is encouraged and supported. Many graduates of the program matriculate into doctoral programs in pharmacology, pharmacy, and biochemistry.

methods beyond which is taught in introductory organic chemistry. Once candidate ligands are synthesized, their effectiveness is tested. Collaboration is fostered as students work within biochemistry to produce the target enzyme, establish a valid assay method, and then screen new compounds for enzyme inhibition. Students have used viral N1 neuraminidase or purified recombinant enzyme with a published fluorometric assay method.6 Although enzyme assay kits for in vitro testing are available from companies, such as Applied Biosystems,7 purified enzymes, proteins, antibodies, and so forth may be available from the ATCC (American Type Culture Collection)8 or BEI Resources (Biodefense and Emerging Infections research resources).9 Established by the National Institute of Allergy and Infectious Diseases (NIAID), BEI provides reagents free of charge to registered users.



CONCLUSION Undergraduate research is a vital part of early education and provides critical skills necessary to prepare young minds to enter graduate school, medical school or industry. Drug discovery, a field typically left to the commercial realm as well as graduate and medical institutions, can be an effective pedagogical tool at an undergraduate institution. Although undergraduate medicinal chemistry research may not be unique, a search of the literature did not find a similar compilation of pedagogy and resources. Hopefully, the experiences and tips contained herein encourage faculty to engage undergraduates in this highly relevant and interdisciplinary area of research.



FUNDING FOR THE STUDENT RESEARCH PROGRAM Although aspects of the above process may be supported by intramural budgets, external funding for undergraduate research is beneficial. The Camile and Henry Dreyfus Foundation10 and Research Corporation11 support undergraduate research. The National Science Foundation12 targets undergraduate research with the RUI (research at undergraduate institutions) and REU (research experiences for undergraduates) programs.13−15 Applications may also be submitted to private institutions such as the Alfred P. Sloan Foundation16 and the Arnold and Mabel Beckman Foundation.17 Projects that are overtly healthrelated should be submitted to the National Institutes of Health (NIH).18 Although the NIH does not have a specific program for undergraduate institutions, the AREA (academic research



AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. B

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ACKNOWLEDGMENTS This work is funded in part by NSF grant 0910524. We are indebted to Scott Hill for his initiation of Medicinal Chemistry at Alma College.



REFERENCES

(1) (a) The PyMOL Molecular Graphics System, Version 1.5.0.4l; Schrödinger, LLC, New York. (b) (Mac)PyMOL. http://www.pymol. org (accessed Oct 2012). (2) Morris, G. M.; Goodsell, D. S.; Halliday, R. S.; Huey, R.; Hart, W. E.; Belew, R. K.; Olson, A. J. J. Comput. Chem. 1998, 19, 1639−1662. (3) AutoDock. http://autodock.scripps.edu (accessed Oct 2012). (4) ZINC. http://zinc.docking.org (accessed Oct 2012). (5) Irwin, J. J.; Shoichet, B. K. J. Chem. Inf. Model. 2005, 45, 177− 182. (6) Potier, M.; Mameli, L.; Belisle, M.; Dallaire, L.; Melancon, S. B. Anal. Biochem. 1979, 94, 287−296. (7) Applied Biosystems. http://www.appliedbiosystems.com (accessed Oct 2012). (8) ATCC (American Type Culture Collection), http://www.atcc. org (accessed Oct 2012). (9) BEI Resources (Biodefense and Emerging Infections research resources), http://www.beiresources.org (accessed Oct 2012). (10) Dreyfus Foundation. http://www.dreyfus.org (accessed Oct 2012). (11) Research Corporation. http://www.rescorp.org (accessed Oct 2012). (12) National Science Foundation. http://www.nsf.gov (accessed Oct 2012). (13) Karukstis, K. J. Chem. Educ. 2010, 87, 245−246. (14) Karukstis, K. J. Chem. Educ. 2006, 83, 1119−1120. (15) Wink, D. J. J. Chem. Educ. 2000, 77, 1549. (16) Alfred P. Sloan Foundation. http://sloan.org (accessed Oct 2012). (17) Arnold and Mabel Beckman Foundation. http://www.beckmanfoundation.com (accessed Oct 2012). (18) The National Institutes of Health. http://www.nih.gov (accessed Oct 2012).

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