| Syllabus |

CHEM.789.03 - Rational Drug Design -- Cheminformatics Online Course, Spring 2017 Herbert J. Bernstein () Assignments

This is the assignments page for CHEM789.03 -- Rational Drug Design -- Cheminformatics, 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 CHEM78903S17, e.g. http://yayahjbCHEM78902S17.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, Get the text book and start reading. We will wait until next week to formally assign specific pages and exercises, but the sooner you start, the easier it will be.
  • 6. Read the syllabus
  • 7. Read on the web about CIF, CML, SMILES and InChi. For CIF, look at the documentation and software at http://www.iucr.org/resources/cif/ and read the original paper on CIF at http://scripts.iucr.org/cgi-bin/paper?es0164 For CML look at http://www.xml-cml.org/ and read the paper at http://pubs.rsc.org/en/content/articlehtml/2001/nj/b008780g For SMILES look at the wikipedia article at https://en.wikipedia.org/wiki/Simplified_molecular-input_line-entry_system and read the paper at http://pubs.acs.org/doi/pdf/10.1021/ci00057a005 For InCHI read the wikipedia article at https://en.wikipedia.org/wiki/International_Chemical_Identifier and the paper at http://jcheminf.springeropen.com/articles/10.1186/s13321-015-0068-4
  • 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, or 13.5 to 18 hours per week for 10 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 Karthikeyan, Vyas text, read from the beginning through the end of chapter 2 (pages vii through 129). You will find several free and commercial tools described. Download and install each of the free tools.
  • 3. Go to the entry for DMSO in the Cambridge Structural Database at https://summary.ccdc.cam.ac.uk/structure-summary?refcode=DMETSO and follow the links to download the CIF. This is the source of the image displayed by CCDC. We will have discussed free tools to display CIFS in the class e-meeting. Use MarvinSketch to draw the same molecule. Do careful research on the use of DMSO in transdermal drug delivery. Write a 15 slide presentation on the use of transdermal drug delivery with DMSO based on your research. Be sure to use the drawings you have done to help illustrate the presentation. Post your presentation to your blog and be prepared to present it during an unpcoming e-meeting.
  • 4. Using the research you have done above, start a bibliography on transdermal drug delivery and post the bibliography to your blog. Note that you will be doing other topical bibliographies. Your may wish to make use of reference management software.
  • 5. Download and read http://www.sciencedirect.com/science/article/pii/S2001037014600398, the mini-review article, [Lounnas, Valre, 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.]. We will return to the issues in this article later in the course. Be sure to keep the article. For the moment, write notes about what you learn from it in your blog.
• 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. In the Karthikeyan, Vyas text, reread chapter 2 and then read through the end of chapter 3 (through page 194). You will find several free and commercial tools described. Download and install each of the free tools. Be sure to install R
  • 3. Use Pubchem and other ligand databases to build a library of as many analgesics (painkillers) as you can find in the time available. You should try to find at least three representatives of each of the following the classes: NSAIDs, COX-2 inhibitors, Alcohol. For each representative your must have at least the SMILES string, but you should also try to get a full three-dimensional structure. For each of those 9 molecules gather as much information as you can find on toxicity as determined experimentally for that molecule, and as much as you can find on the relationship between structure and toxicity for each of those molecules. Write a coherent, well-organized 2000 word essay discussing first the theoretical predicitions of toxicity for these molecules based purely on structure-proterty relationships, and then the correlation between those predictions and experimental (especially in vivo) determinations of toxicity for those same molecules. If you have to you may confine your definition of toxicity to the issue of mortality, but especially for these drugs, it would be better to also look at morbidity. Use of the tools you have downloaded to generate figures to illustrate your points. Be sure to post your paper.
  • 4. Use and add to your research from last time to consider the question of the impact of transdermal transport molecules such as DMSO on estimates of toxicity. Write a 15 slide presentation on this topic. Be sure to post your presentation and to add to the bibliography you started last time.
  • 5. Go back to http://www.sciencedirect.com/science/article/pii/S2001037014600398, the mini-review article, [Lounnas, Valre, 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.]. Look at the rest of this assignment and consider the question of what are the practical consequences for estimating toxicity in moving from experimentation to simulation, and from in vivo to in vitro to in silico in drug design. Form a preliminary opinion on the basis of what you know now and post that to your blog. Your opinion may change during the semester. If it does, feel free to update what you say now, but please keep a trace of the evolution of your opinions in this matter on your blog.
• 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. In the Karthikeyan, Vyas text, reread chapter 3 and then read through the end of chapter 4 (through page 269). You will find several free and commercial tools described. Download and install each of the free tools. Be sure to install and try Autodock Vina and PharmaGist.
  • 3. Refer back to and improve the library of analgesics you build for the previous assignment and build a small companion library of macromolecular targets for those analgesics. Use autodock vina to estimate affinities for as many combinations of analgesis and target as you have time for.
  • 4. You now have a small set of affinities and toxicities for a few analgesics. Write a well-researched 2000 word essay on what role, if any, such information might have in the design of a new analgesic.
  • 5. Take what you have learned thus far and prepare a 15 slide course project preliminary proposal for the structure-based in silico rational design of a useful, druggable ligand relevant to a disease of your choice. Be as specific as possible about the tools and techniques you would like to use.
• 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. In the Karthikeyan, Vyas text, read chapter 4 (through page 269) and, to plan ahead, read chapter 5 (through page 316). You will find several free and commercial tools described in chapter 4. Download and install each of the free tools. If you have not already done so, be sure to install and try Autodock Vina and PharmaGist.
  • 3. Pick a disease for which you would like to design a drug, and for which at least ten different effective drugs with available 3D strucures are already known and for which at least one specific target macromolecule with a full 3D structure is known. Use Autodock to select at least five drugs that bind to the same binding site. Use PharmaGist to compute a pharamcophore from those five drugs.
  • 4. Prepare a 15 slide presentation on the results of your pharmacophore efforts.
  • 5. Do some research and prepare a 2000 word paper on how your could find or design new ligands to be tested as new better potential drugs for the same binding site. 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.
  • 6. Start a critical bibliography for your drug design project.
  • 7. Prepare a report on everything you do and learn for this assignment, post it to your blog and email the URL to the instructor.
• 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 completed assignments 1, 2, 3, 4, and 5. Late-Start Students: Be sure to have completed assignments 1, and 5. Email the instructor your blog and website URLs after updating them for this assignment.
  • 2. In the Karthikeyan, Vyas text, read chapter 5 (through page 361) and, to plan ahead, read chapter 6 (through page 374). In chapter 5, you will find several free and commercial tools described. Download and install each of the free tools.
  • 3. Read https://academic.oup.com/nar/article/42/D1/D1091/1047263/DrugBank-4-0-shedding-new-light-on-drug-metabolism on DrugBank 4 and prepare a 2000 word paper on the DrugBank 4 using specific issues from your project in particular to illuminate your discussion.
  • 4. For each ligand in your project for which you have autodock results for the most promising site, you are to gather as much information as you can on absorption, distribution, metabolism, excretion and toxicity (ADMET) and other quantitative structure activity relationships (QSAR). Prepare a 15 slide presentation on your results. Be sure to consider how you would optimize both in the basis of ADMET and on the basis of your Autodock results.
  • 5. Update your critical bibliography for your drug design project.
  • 6. Prepare a report on everything you do and learn for this assignment, post it to your blog 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 that this assignment overlaps spring break.
  • 1. Non-Late-Start Students: If you have not already done so, be sure to have completed assignments 1, 2, 3, 4, 5, and 6. 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. In the Karthikeyan, Vyas text, read chapter 6 (through page 374) and, to plan ahead, read chapter 7 (through page 414).
  • 3. For your project you should now have at least one appropriate target active site and several well-characterized ligands that can dock in that site. Use any or all of the tools or databases you have looked at to find or create one, new, different ligand that demonstrates stronger binding affinity according to autodock, and is no worse in terms of ADMET. Alternatively you may hold binding affinity constant and decrease estimated toxicity. Prepare a 15 slide presentation on you progress on this aspect of your project.
  • 4. Prepare a detailed, properly referenced report (use your critical bibliography) on the status of your project. There is no upper limit to the length of this report because it will simply grow from this point on until you are done, but it should be at least 2000 words long, not counting the references.
  • 5. Prepare a report on everything you do and learn for this assignment, post it to your blog 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 completed assignments 1, 2, 3, 4, 5, 6, and 7. 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. In the Karthikeyan, Vyas text, read chapter 7 (through page 414) and, to plan ahead, read chapter 8 (through page 449).
  • 3. For your project you should now have at least one appropriate target active site, several known characterized ligands, and at least one ligand of your own design that you propose on the basis of in silico investigations as better than what was available at the start of your project. Carefully consider the ADMET characteristics of your ligand, and do a literature search for each characteristic and try to find an in vitro protocol to confirm the in silico estimates. Prepare a 15 slide presentation on your efforts. You do not have to perform the in vitro confirmation, just report on how it can be done.
  • 4. Prepare a detailed, properly referenced (using your critical bibliography) report on the status of your project. There is no upper limit to the length of this report because it will simply grow from this point on until you are done, but it should now be at least 4000 words long, not counting the references.
  • 5. Prepare a report on everything you do and learn for this assignment, post it to your blog 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 completed assignments 1, 2, 3, 4, 5, 6, 7 and 8. Email the instructor your blog and website URLs after updating them for this assignment.
  • 2. In the Karthikeyan, Vyas text, read chapter 8 (through page 449) and, to plan ahead, read chapters 9 and 10 (through page 528).
  • 3. For your project you should now have at least one appropriate target active site, several known characterized ligands, and at least one ligand of your own design that you propose on the basis of in silico investigations as better than what was available at the start of your project. You should also have a proposal to test the ADMET properties of your ligand in vitro. Now it is time to look for gaps in your project. In a 15 slide presentation, present a checkist of what would still need to be done get from where you are now to having a viable drug ready for human trials.
  • 4. Prepare an updated detailed, properly referenced (using your critical bibliography) report on the status of your project. There is no upper limit to the length of this report because it will simply grow from this point on until you are done, but it should now be at least 6000 words long, not counting the references.
  • 5. Prepare a report on everything you do and learn for this assignment, post it to your blog 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 completed assignments 1, 2, 3, 4, 5, 6, 7, 8, and 9. Email the instructor your blog and website URLs after updating them for this assignment.
  • 2. Finish the Karthikeyan, Vyas text.
  • 3. Read the wikipedia article on druglikeness, https://en.wikipedia.org/wiki/Druglikeness. Last time you looked for gaps in your project and made a checklist of what would still need to be done to get to having a viable drug ready for human trials. Now add to that checklist a section on druglikeness, and prepare a 15 slide presentation on the druglikeness of your ligand, giving the results you know so far and what you would need to do to be sure of how druglike your ligand is.
  • 4. Prepare an updated detailed, properly referenced (using your critical bibliography) report on the status of your project. There is no upper limit to the length of this report because it will simply grow from this point on until you are done, but it should now be at least 8000 words long, not counting the references.
  • 5. Prepare a report on everything you do and learn for this assignment, post it to your blog 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 completed assignments 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. Email the instructor your blog and website URLs after updating them for this assignment.
  • 2. You should have finished the Karthikeyan, Vyas text. Now go back through it and other background resources and gather the necessary citations and descriptions for the software and methods you are using for your project that are not already in your critical bibliography, and add them to your ciritical bibliography, which, at the end of this process, should be close to complete. Add the current best version to your blog or web site and submit the URL for your project criticial bibliography for grading, no later that 17 April 2017. In addition, prepare a 10 slide presentation of the most important citations in that bibliography to present at the 18 April e-meeting.
  • 3. Then prepare a 10 slide introduction to your project explaining in summary form what problem you are trying to solve, the methods you are applying to solve that problem, and the results of that effort so far and what remains to be done. Be very careful to use proper citations to your critical bibliography from within your introduction in the form [authors(s) date]. Prepare 1-3 more slides giving an outline to what you will present in early May in 35 more slides that make your final project presentation total 45 slides, not counting the critical bibliography slides, not counting the outline slides, not counting reference slides and not counting any additional acknowledgement slides. You will also present the 11-13 slides at 18 April e-meeting.
  • 4. Prepare an updated detailed, properly referenced (using your critical bibliography) report on the status of your project. There is no upper limit to the length of this report because it will simply grow from this point on until you are done, but it should now be at least 10000 words long, not counting the references.
  • 5. Prepare a report on everything you do and learn for this assignment, post it to your blog 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 completed assignments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11. Email the instructor your blog and website URLs after updating them for this assignment.
  • 2. The critical bibligraphy you will have submitted on 17 April will have been evaluated and returned to you by 21 April. Update your critical bibliography in response to that evaluation and any additional material you have that is appropriate to that bibliography
  • 3. Prepare at least 18 more slides of the 35 pending slides for your final project presentation, and be ready to present them during the 25 April e-meeting.
  • 4. Prepare an updated detailed, properly referenced (using your critical bibliography) report on the status of your project. There is no upper limit to the length of this report, but there is not specific increment needed now. You may put your effort into additional words or into revising the words you already have.
  • 5. Prepare a report on everything you do and learn for this assignment, post it to your blog and email the URL to the instructor.
  • 6. Note that you will be submitting your final project report for grading in the next assignment. After that you will be preparing for the final exam.
• Assignment 13: Assigned, Monday 24 April 2017; due Monday 1 May 2017.
  
  • 1. If you have not already done so, be sure to have completed assignments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12. Email the instructor your blog and website URLs after updating them for this assignment.
  • 2. Prepare a one-page, 400 word summary descrtiption of the process of rational drug design targetted to a general scientific audience.
  • 3. Finish your 45 slide project presesntation and your project report with your critical bibliography.
  • 4. Prepare a report on everything you do and learn for this assignment, post it to your blog and email the URL to the instructor.
• Assignment 14: Assigned, Monday 1 May 2017; due Monday 8 May 2017.
  
  • 1. At 2 May e-meeting, we will have presented your hopefully final project, and will finish at the the 9 May 2017 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.