| Syllabus |

BIOL.689.01 - Rational Drug Design -- Cheminformatics Online Course, Spring 2017 Herbert J. Bernstein () Assignments

This is the assignments page for BIOL.689.01 -- Rational Drug Design -- Bioinformatics, an online course at Rochester Institute of Technology, for Spring 2017. If you are a student in the course, please return to this page every week to look for updates. Additional assignments will be posted no later than Sunday evenings so that they are available no later than Monday morning.

Schedule adjustments for late start students: Students who join the course at the end of February will do assignment 1 in parallel with assignment 5, assignment 2 in parallel with assignment 6, assignment 3 in prallel with assignment 7 and assigmment 4 in parallel with assignment 8. Assignments 9 and following will not be doubled up.

• Assignment 1: Assigned, Monday 23 January 2017; due Monday 30 January 2017.
  Late Start Assignment 1: Assigned Monday 20 February 2017; due Monday 27 February 2017 in parallel with assignment 5.
  • 1. Sign up for Skype (https://support.skype.com/en/faq/FA12413/how-do-i-create-a-skype-account)and send a contact request to the instructor, yayahjb
  • 2. Sign up for a Google account (https://accounts.google.com/signup), and, using your gmail account, send your gmail address to the instructor at his gmail address ()
  • 3. Using your Google account, start a blog for your work in this course (see https://www.blogger.com/). Blogs use a global name space. To avoid conflicts, begin the name for your blog with your Google ID followed immediately by the name BIOL689S17, e.g. http://yayahjbBIOL689S17.blogspot.com/
  • 4. Using your Google account, start a personal course web page on which to post reports and projects for this course. If you already have a public web page, you may use a subpage of that web page instead, provided the reports and projects will be public. You must make your blog posts and all your papers and presentations public. Be very careful about what you post, both in terms of respecting the intellectual property of others and in terms of being very sure that what you post is material that you are willing to make public. This may seem daunting, but you must get used to it if you are every to be successful at scientific publication.
  • 5. There is no formal text for this course. Instead, please download and read http://www.sciencedirect.com/science/article/pii/S2001037014600398, the mini-review article, [Lounnas, Valère, Tina Ritschel, Jan Kelder, Ross McGuire, Robert P. Bywater, and Nicolas Foloppe. "Current progress in Structure-Based Rational Drug Design marks a new mindset in drug discovery." Computational and structural biotechnology journal 5, no. 6 (2013): 1-14.], and start reading it. We will wait until next week to formally assign specific tasks based on this article, but the sooner you start, the easier it will be.
  • 6. Read the syllabus
  • 7. Read on the web the macromoecular structure and sequence formats. For the Protein Data Bank (PDB), look at the documentation and software at http://pdb101.rcsb.org/learn/guide-to-understanding-pdb-data and http://www.rcsb.org/pdb/static.do?p=software/software_links/molecular_graphics.html and read the original paper on the PDB at http://onlinelibrary.wiley.com/doi/10.1111/j.1432-1033.1977.tb11885.x/epdf [Bernstein, Frances C., Thomas F. Koetzle, Graheme JB Williams, Edgar F. Meyer, Michael D. Brice, John R. Rodgers, Olga Kennard, Takehiko Shimanouchi, and Mitsuo Tasumi. "The protein data bank." European Journal of Biochemistry 80, no. 2 (1977): 319-324.] You will have read a little about mmCIF in the PDB documentation. You should also read the original mmCIF paper at http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.14.5944&rep=rep1&type=pdf" [Bourne, Philip E., Helen M. Berman, Brian McMahon, Keith D. Watenpaugh, John D. Westbrook, and Paula MD Fitzgerald. "[30] Macromolecular crystallographic information file." Methods in enzymology 277 (1997): 571-590.] For FASTA sequence format look at http://blast.ncbi.nlm.nih.gov/blastcgihelp.shtml and read the paper at http://www.faculty.virginia.edu/wrpearson/papers/lipman_pearson_sci85.pdf, [Lipman, David J., and William R. Pearson. "Rapid and sensitive protein similarity searches." Science 227, no. 4693 (1985): 1435-1441.] For additional sequence formats, see https://www.genomatix.de/online_help/help/sequence_formats.html. We will look deeper into the literature in the next assignment, but now it is time to digest what you have seen to this point.
  • 8. Write a 2000 word essay comparing and contrasting the formats you just read about.
  • 9. Arrange a regular schedule of weekly e-meetings with the instructor.
  • 10. Describe everything you have done for this course up to this point in your course blog.
  • Yes, this assignment is a lot of work, but if you put off doing that work, you will find yourself that much further behind next week, when there will be an even more demanding assignment. You must get used to the idea that for every 3-credit college course you take, you must put in a solid 9 to 12 hours per week for 15 weeks. It takes more than 10,000 hours to become expert at anything. The 135 to 180 hours you will put in for this course is just a small down-payment on those 10,000 hours.
• Assignment 2: Assigned, Monday 30 January 2017; due Monday 6 February 2017.
  Late Start Assignment 2: Assigned Monday 27 February 2017; due Monday 6 March 2017 in parallel with assignment 6.
  • 1. Non-Late-Start Students: If you have not already done so, be sure to have completed assignment 1. Late Start Students: Be sure to have compled assignments 1 and 5. Email the instructor your blog and website URLs.
  • 2. In the Lounnas et al. paper it says "One could argue that the vast resources invested in HTS could have been used more productively to characterize how leads interact with the target receptor, to inform their efficient optimization. In response, many research groups throughout the world have dedicated efforts toward structure based drug design (SBDD) and virtual ligand screening (VLS), as the most scientifically promising approaches to identify ligands for pharmaceutical targets [15-20]." Read [15] http://www.bio-itworld.com/BioIT_Article.aspx?id=86836. Do research on what are the following question: When using 3-dimensional structures of macromolecules in structure based drug design obtained from the PDB, what quantitative measures are available to assess the accuracy of the stuctures being used? Prepare slides for a 15 minute presentation on this topic. Post the slides to your blog and be prepared to present them at an upcoming e-meeting.
  • 3. Go back to the papers in the prior assignment on the two formats used by the PDB -- the old PDB fixed-field 80-columns format, and the new mmCIF format. Using those papers and any other relevant papers you can find, prepare a 2000 word essay comparing those two formats on one very specific issue. If you have two structures that you needed to compare for structural similarity (homology), how would you do that comparison, and in which of the two formats would it be easier to do that comparison. Note that this question is just one of many similar questions relating to the impact of the choice of format in helping or hindering use of the data to answer structural questions.
  • 4. Update your blog and web site with the work you do for this assignment and any questions you may have.

• Assignment 3: Assigned, Monday 6 February 2017; due Monday 13 February 2017.
  Late Start Assignment 3: Assigned Monday 6 March 2017; due Monday 20 March 2017 in parallel with assignment 7.
  • 1. Non-Late-Start Students: If you have not already done so, be sure to have completed assignments 1 and 2. Late Start Students: Be sure to have completed assignments 1, 2, 5, and 6. Email the instructor your blog and website URLs after updating them for this assignment.
  • 2. As we noted last time, in the Lounnas et al. paper it says "One could argue that the vast resources invested in HTS could have been used more productively to characterize how leads interact with the target receptor, to inform their efficient optimization. In response, many research groups throughout the world have dedicated efforts toward structure based drug design (SBDD) and virtual ligand screening (VLS), as the most scientifically promising approaches to identify ligands for pharmaceutical targets [15-20]." Read [15] http://www.bio-itworld.com/BioIT_Article.aspx?id=86836. Note that the focus in this statment is on screening ligands. Carefully consider the question of when it might be useful to fix the ligand and screen the targets instead (hint: think about drug side effects). Do research on targets to which aspirin binds to illustrate a 15 minute presentation on this topic.
  • 3. Virtual screening is complicated by polymorphic ligands and targets. To get a sense of the issues involved, do research on whether there are or are not multiple docked conformations of aspirin and of multiple conformations of the docking sites for aspirin and discuss in a 2000 word essay. Illustrate your paper with figures you draw using software you have dowloaded.
  • 4. Update your blog and web site with the work you do for this assignment and any questions you may have.
• Assignment 4: Assigned, Monday 13 February 2017; due Monday 20 February 2017.
  Late Start Assignment 4: Assigned Monday 20 March 2017; due Monday 27 March 2017 in parallel with assignment 8.
  • 1. Non-Late-Start Students: If you have not already done so, be sure to have completed assignments 1, 2 and 3. Late-Start Students: Be sure to have completed assignments 1, 2, 3, 5, 6 and 7. Email the instructor your blog and website URLs after updating them for this assignment.
  • 2. Download and read http://nrl.northumbria.ac.uk/29119/1/ISon2016-08-BallwegBronowskaVickers.pdf. Prepare a 2000 word essay on the role of molecular visualization in rational drug design in which you consider the importance (or lack of importance) of the use of motion, color, stereo, sound and other visualization feature extensions in this application.
  • 3. Download and read http://pubs.acs.org/doi/pdf/10.1021/jm00399a006 on "Designing Ligands for a Receptor Binding Site" and http://onlinelibrary.wiley.com/doi/10.1002/jcc.21334/full on Autodock Vina, do some further research on a particular disease pathway, find an interesting macromolecule active site and write a 15-slide preliminary course project proposal on the design of a ligand that would be a likely lead for binding to that site. This does not mean you have to do your project based on that particular site for your project, just that you are gaining a sense of part of what needs to be done to design a drug.
  • 4. Update your blog and web site with the work you do for this assignment and any questions you may have.
• Assignment 5: Assigned, Monday 20 February 2017; due Monday 27 February 2017.
  Late Start students: Do in parallel with Assignment 1.
  • 1. Non-Late-Start students, if you have not already done so, be sure to have done assignments 1, 2, 3 and 4. Email the instructor your blog and website URLs after updating them for this assignment.
  • 2. Pick a disease for which you would like to find a drug, and for which at least three different macromolecular targets having structures in the PDB are available to treat the disease with known drugs that will bind to known binding sites on those targets.
  • 3. Prepare a 15 slide presentation on your research in finding the targets, the active sites and the known drugs.
  • 4. Do some research and prepare a 2000 word paper on how your could find other ligands with known 3D stuctures to be tested as new better potential drugs for the same binding sites. Include a plan on how you would define and test whether your new drug would truly be better. Be sure your paper is fully and properly researched with appropriate literature citations.
  • 5. Consider the question of whether you could treat the disease by modifying the sequences of the targets. Be prepared to discuss in the next class.

• Assignment 6: Assigned, Monday 27 February 2017; due Monday 6 March 2017.
  Late Start students: Do in parallel with Assignment 2.
  • 1. Non-Late-Start students, if you have not already done so, be sure to have done assignments 1, 2, 3, 4 and 5. Late-Start students, if you have not already done so, be sure to have done assignments 1 and 5
  • 2. Read Hoque, Injamul, Arkendu Chatterjee, Somenath Bhattacharya, and Raj Biswas. "An Approach of Computer-Aided Drug Design (CADD) Tools for In Silico Pharmaceutical Drug Design and Development." Int. J. Adv. Res. Biol. Sci 4, no. 2 (2017): 60-71 ( http://www.ijarbs.com/pdfcopy/feb2017/ijarbs9.pdf. Prepare a 2000 word essay on the paper, including consideration of how you can apply any of the approaches described to your own term project.
  • 3. For the disease of your choice (which you may make the same or different as in assignment 5), identify three different macromolecular targets having structures in the PDB with known drugs that will treat the disease that will bind to known binding sites on those targets, and for which you have identified other ligands with known 3D structures. Use Autodock to extimate binding affinities for both the known drugs and the other ligands you have identified and prepare a 15 slide presentation on the results.
  • 4. Start a critical bibliography to supply references for your project.
  • 5. Update your blog and/or web page with all work done for the course so far and email the URL to the instructor.

• Assignment 7: Assigned, Monday 6 March 2017; due Monday 20 March 2017.
  Late Start students: Do in parallel with Assignment 3. Note this assignment overlaps spring break.
  • 1. Non-Late-Start students, if you have not already done so, be sure to have done assignments 1, 2, 3, 4, 5, and 6. Late-Start students, if you have not already done so, be sure to have done assignments 1, 2, 5, and 6
  • 2. Find one good paper that is available for free as a PDF online, that discusses drug therapies for the disease in your project and prepare a 2000 word paper discussing the relationship between the drug therapies discussed in that paper and the drugs you have looked at this far.
  • 3. Prepare a 15 slide presentation discussing a detailed surface map of your primary disease therapy target with annotations on charge, hydrophobicity, hydrophilicity, and/or other surface properties that relate to the action of at least one proposed drug in that context.
  • 4. Extend your critical bibliography for your project.
  • 5. Update your blog and/or web page with all work done for the course so far and email the URL to the instructor.

• Assignment 8: Assigned, Monday 20 March 2017; due Monday 27 March 2017.
  Late Start students: Do in parallel with Assignment 4.
  • 1. Non-Late-Start students, if you have not already done so, be sure to have done assignments 1, 2, 3, 4, 5, 6, and 7. Late-Start students, if you have not already done so, be sure to have done assignments 1, 2, 3, 5, 6 and 7
  • 2. Download and read http://pubs.acs.org/doi/pdfplus/10.1021/tx200211v (Improving Drug Candidates by Design: A Focus on Physicochemical Properties As a Means of Improving Compound Disposition and Safety, by Nicholas A. Meanwell) and prepare both a 2000 word paper and a 15 slide presentation on how to address the ADMET properties of the most promising ligand for your project.
  • 3. Extend your critical bibliography for your project.
  • 4. Update your blog and/or web page with all work done for the course so far and email the URL to the instructor.

• Assignment 9: Assigned, Monday 27 March 2017; due Monday 3 April 2017.
  • 1. If you have not already done so, be sure to have done assignments 1, 2, 3, 4, 5, 6, 7, and 8.
  • 2. Download and read http://www.sciencedirect.com/science/article/pii/S1359644616302975 (The many roles of molecular complexity in drug discovery, by Oscar Méndez-Lucio and José L. Medina-Franco) and prepare both a 2000 word paper and a 15 slide presentation on how to address the complexity issues of the most promising drug for your project.
  • 3. Extend your critical bibliography for your project.
  • 4. Update your blog and/or web page with all work done for the course so far and email the URL to the instructor.

• Assignment 10: Assigned, Monday 3 April 2017; due Monday 10 April 2017.
  • 1. If you have not already done so, be sure to have done assignments 1, 2, 3, 4, 5, 6, 7, 8 and 9.
  • 2. Read the wikipedia article on CRISPR, https://en.wikipedia.org/wiki/CRISPR and http://www.sciencedirect.com/science/article/pii/S2452310017300410 (Progress towards precision functional genomics in cancer by Cory M. Johannessen and Jesse S. Boehm) and prepare both a 2000 word paper and a 15 slide presentation on the likely future applications of CRISPR/CAS9 to rational drug design and the ethics of those applications.
  • 3. Extend your critical bibliography for your project.
  • 4. Update your blog and/or web page with all work done for the course so far and email the URL to the instructor.

• Assignment 11: Assigned, Monday 10 April 2017; due Monday 17 April 2017.
  • 1. If you have not already done so, be sure to have done assignments 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.
  • 2. It is time to start completing the essential elements of your project report. Go through all the materials you have used so far an prepare as close to a final critical bibliography for your project as possible. List papers, books, software and software. Prepare a 10 slide presentation on the most important aspects of you bibliography and be prepared to present those slides on 18 April.
  • 3. Read the Nature article, "Imaging with Antibodies" by Rosie Mestel, http://www.nature.com/nature/journal/v543/n7647/pdf/543743a.pdf which discusses immunoPET imaging, which is one of an increasingly important range of nuclear medicine techniques that impact rational drug design. Consider the possible role of radiotracers in your own project and prepare 10 slides on the subject.
  • 4. Prepare your project report introduction and critical bibliography for preliminary grading. Your introduction should summarize the problem you are solving, giving the background with citations from your critical bibliograpraphy, a summary of the methods you are applying and the results so far. Post the report to your blog or web page and email the URL to the instructor for grading. Prepare 10 slides on this part of your report to present on 18 April. Also prepare 1-3 more slides outlining 35 more slides that will give details of methods, results, conclusions and future plans. Don't count references, acknowledgements, or other supplementary material in the total of 45 slides you are planning.
  • 5. Update your blog and/or web page with all work done for the course so far and email the URL to the instructor.

• Assignment 12: Assigned, Monday 17 April 2017; due Monday 24 April 2017.
  • 1. If you have not already done so, be sure to have done assignments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11.
  • 2. Read the Nature article, "Join the hunt for biomarkers," by Paul Smaglik, http://www.nature.com/naturejobs/2017/170330/pdf/nj0506.pdf. Then consider the question of where one could apply an understanding of biomarkers to the process of rational drug design. You do not have to prepare specific slides, but be prepared to discuss.
  • 3. Prepare 18 of the remaining slides for a presentation on your project. Also prepare half of the remaining report content. You will be submitting your full project report for grading the first week of May, and presenting a full 45 minute presentation on your project that week.
  • 4. Update your blog and/or web page with all work done for the course so far and email the URL to the instructor.

• Assignment 13: Assigned, Monday 24 April 2017; due Monday 1 May 2017.
  • 1. If you have not already done so, be sure to have done assignments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12.
  • 2. Using your project critical bibliography and your blog notes, and the work you have done on your project, prepare a one-page, 400 word summary of the process of rational drug design targetted to a general scientific audience.
  • 3. Finish your 45-slide project presentation and your project report for preliminary grading. If your get both of these in on time, there will be time for preliminary comments and you will have a chance to revise possibly for a better grade.
  • 4. Update your blog and/or web page with all work done for the course so far and email the URL to the instructor.

• Assignment 14: Assigned, Monday 1 May 2017; due Monday 8 May 2017.
  • 1. At the 2 May e-meeting, you will have presented your hopefully final project, but if there are any remaining issues, please take care of them before the 9 May e-meeting.
  • 2. The remaining time for the 9 May e-meeting will be used to review for the final. The final will be an on-line take-home exam. You will be given the URL for the final by Monday, 15 May 2017 and it will be due by Wednesday, 17 May.