please make the final project based on the project proposal and the 7 labs
Microsoft Word - 3. Final Project - Assignment - V3.docx Final project overview (375 points) Due: Friday June 12, 2020 by 5:00 PM Imagine that you want to make a new drug. Where do you start? One place that many labs start with is computer modeling. The final project in this class is centered around this idea – that you are a researcher looking to find a new drug for a disease of your choice and like any researcher you must provide justification for why your drug is potentially better. For this project you will design two new drug candidates and make predictions about their activity and other properties using the computational tools that were introduced in Labs 1-7 and previous lab projects. At this point in the course you have found a target protein and a candidate drug family in the previous project assignments, now your next steps are to use all of the tools you have learned from this class to predict how well your drug candidates interact with the target. The final project can broadly be broken into three parts: 1) The first step is docking your drug candidates into your target, and then the second step designing two new small molecules from one of your candidates. The designs must have better scores than the original. One design must be proposed using Brood, the other must be hypothesis driven – i.e. I propose that adding an alcohol group at a position will make a new interaction with the protein and give a better score. 2) Second, we need to figure out if there is a possibility for beneficial and/or non- beneficial off-target effects of your drug using the techniques introduced in lab 2. Specifically, we are looking for you to address at least ONE of these three key questions: 1. Is there a beneficial organism that has a homologous protein? If no, what does that mean about the potential of your molecule to affect that organism? If yes, based on the sequence and structural alignment, do you expect your compound to bind to the beneficial organism’s protein and why? Finally, what do you think that means for the organism? 2. Is there a pathogenic organism that has a homologous protein? If no, what does that mean about the potential of your molecule to affect that organism? If yes, based on the sequence and structural alignment, do you expect your compound to bind to the pathogenic organism’s protein, and why? Finally, what do you think that means for the organism? 3. If you wanted to test your protein in pre-clinical animal studies, would you expect the organism to be a good model system based on the presence/absence of a homologous protein in common animal models, and why? Be sure to look at the Important Tips file for additional guidance in how to answer this question. Also, if you are feeling ambitious and enjoying the project, an additional +10 bonus points will be awarded if you perform 2 analysis correctly; and +20 if all three are done correctly. 3) You must turn in a final report in which you explain in detail why you think that your proposed drug candidates show promise. Your argument must be supported by computational evidence that you obtain yourself. In your final report, you must clearly describe the calculations that provide support for your proposed molecule(s) being leads, and the significance of your results. You should also describe your level of confidence in these results—i.e. which do you feel are most reliable and which are more tentative. Your report will be graded on the thoroughness of the computational studies you completed as well as the quality of argument you make—i.e. the quality and quantity of evidence you provide in support of your argument from both the primary literature on your biological target and your computations. You need to make a strong argument, but you should NOT hide any evidence that might suggest problems with your proposed drug candidate—a balanced argument that provides a reasonable assessment of the likelihood of success is what we are after! While brain storming for potential drug candidates, you should keep in mind Lipinski’s rules, things that affect ADME and toxicity, and things that might make your drug candidate selective for your target over other possible targets. For this project, you do not need to concern yourself with the difficulty of synthesizing the drug candidate you propose, although you should not invent new functional groups! If the project is done well and you enjoyed it, please reach out to your TA about publishing the work you have done. This is novel scientific work and your analysis could lead to the development of novel therapeutics and compounds of interest if the world knows about them. An example of a previous report turned into a publication (before we added section 2) can be found here: https://www.biorxiv.org/content/10.1101/772137v1.abstract HAVE FUN THINKING AND CREATING! Chem 130B Final Project Grading Rubric. I don’t list points for each bullet point because I want to give some flexibility in how you do your grading but there are some bullet points which do have points associated with them. These are areas that I feel are of higher import and as such I want to make sure that they are reflected in their score. Generally, and “A” level-grade is awarded for projects where modeling is correctly run, thoughtfully described reasoning of the results, and presented in a professional manner that looks like it could be a paper in a journal (i.e. high quality images similar to what you saw in the literature report papers your reviewed). A “B” level- grade has properly run simulations, some thought behind results, and with unprofessional presentation (i.e. hard to interpret screenshots). A “C” level-grade and below will be awarded when simulations were run incorrectly and/or the analysis of the results are poorly presented Clarity (65 pts )– ~17% of the grade) – This is also the grammar and language usage portion of the grade and is broken down as follows: • General clarity and is there a good flow to their writing? (minimum 30 pts ) In general, my expectation is that someone who has take 130A (so a person who has all their knowledge, but hasn’t take the course) should be able to read the report and understand what they’re trying to do. If the student does that then they get 90% of the points for general clarity (ie 27 out of 30). If any chemistry student could understand what they are doing, give them 28 out of 30. If a physicist could 29 out of 30 and if anyone could read it (ie, your mom) then give them full credit. • Are they able to clearly tell you what their system of study is and why it is important? • Are the able to connect their system to their target enzyme? • Do they appropriately introduce their drug family? Professionalism (35 points)– ~9% of the grade) These are the points for correct usage of their in text figures and tables along with how professional their images, chem draws and tables are. Also included in this are their captions for their figures. Logic (110 pts)– ~29% of the grade) This is the portion of the grade that examines their choices on what they did and WHY they did it. • Control experiment (minimum 45 pts) Did they run a control experiment by docking the known ligand from their crystal structure into the model of the active site. Did the result actually validate their model? Do they explain what they did and why, when they were building their receptor? • Do they explain where and why they started when exploring for a new possible compounds? • Do they talk about the source of the improved docking score for their new compounds? I want specific reasons like: new h-bonding interaction, better at filling the pocket as represented by a higher sterics score in the docking run, etc. • If they eliminate a drug from their drug family do they talk about why they did it and why it was ok? There are a lot of good reasons to not include a compound when doing this. • Do they “get it.” This is the most open ended but ultimately were they able to demonstrate that they understand what is good about this kind of modeling and what is the limitations or was the student just following the labs in the manual without really engaging. Score (30 pts per compound (60 points total)– ~16% of the grade) The students were told that they needed to find two new compounds. See the table below for how to score their each compounds: Score is this much better (%) Give student this much of points 4 % 3 pts 5 % 15 pts 10 % 24 pts 15 % 27 pts 20% 28 pts 30% 29 pts 35 % + 30 pts Homolog Analysis (75 pts – ~20% of the grade) Was the analysis for at least one homolog (beneficial microbe, pathogenic microbe, or pre-clinical animal model) of the target protein completed and analyzed correctly (homolog search of all organism ID’s provided for the category, sequence alignment with target, structural analysis of binding pocket with new compounds). ***Potential for +20 bonus points of analysis done for all three categories, +10ea*** Citations & Scifinder (30 pts – ~8% of the grade) Are they using correct numerical citations in text and the correct ACS style at the end? Did they upload their citations into the dropbox? Did they check on scifinder that no one has proposed their structure before for the same system? Microsoft Word - Final project Q2 Important Tips.docx Final project Question 2 Important Tips When doing blast instead of searching the nr like we did in lab 2, choose a species group (beneficial, pathogenic or clinical) and search for a single homolog of your target protein using protein BLAST (ID’s given below). Not every organism will have a homolog of your target protein