Drug Design Project Information and Tips CHEM 162B (2010) Part of your grade in Drug Design courses will come from a development of a “Drug Design Project”. Students who have taken Chem162A will be able to continue their project development; students who have not taken Chem 162A can pick one of the projects developed in past and take it further. Students taking Chem 162 during the Winter 2010 will be able accomplish three important milestones toward completing the Project. Part of your grade will be based on your success in completing these milestones. The milestones that you are expected to complete during the Winter of 2010 are: 1) Characterize a validated protein/nucleic acid target for the disease that you are working on. If the target is an enzyme, describe the reaction it catalyzes and the role of the enzyme active site. If the target is not an enzyme, describe in detail its physiological role and mode of operation, with focus on protein-ligand interactions critical for binding. 2) Obtain or create a virtual library of possible drug candidates that are expected to bind to this target and carry out virtual screening to identify best binders. 3) Describe adsorption, distribution, metabolism, excretion, and possible toxicity aspects of your drug candidate(s). If appropriate, propose modifications to improve your drug. You are expected to turn in your work on each milestone by the due dates specified; you’ll automatically receive 3 points per each milestone if you submit a significantly developed work by the due date. You will earn extra 5 points if you submit all milestones by the due date. You will receive feedback on your ideas that will help you to refine your proposal and you will submit the refined proposal on how to meet these four milestones at the end of the quarter. Each milestone in your refined proposal is worth 12 points. In summary, you could earn 50 points if you submit reasonably well developed plans by due dates and will resubmit perfect proposal by the end of the quarter. What is expected in your final write-up? A written report (under eight pages excluding references), with a title, references, lots of graphics that clearly explains your ideas, and structures of compounds. Sections should include: • a background, in which you describe why there is a need for what you are proposing. Briefly discuss current therapies, and include the background about the lead compound, if appropriate. This can be a summary of a previous proposal on the topic you are working on. • a technical description of the work you performed in this course (the three milestones). Write this up similarly to a methods section in scientific publications (e.g. like in the Schapira paper on thyroid hormone receptor screening). • an overview of main results obtained (structures, properties of molecules, predicted binding scores) and their critical analysis. Most of your figures (transition state geometries, electrostatic potential maps, docked poses, schemes for possible metabolic reactions) should be included in this section. • your self-criticism, in which you discuss potential promises and likely limitations of the drug you have designed. Focus on material relevant to these three milestones and do not concern yourself with topics such as cost, manufacturing, and intellectual property issues.Drug Development Milestone I Due date: Thursday, Feb 8, 2010 Characterize a validated protein target for the disease that you are working on As a first part of your project, you are expected to characterize a validated target for the disease you are working on. Visualize the protein that you are targeting and create images of the binding pocket / active site. If ligand-bond structures of the target are available, examine the protein ligand complexes, and discuss main interactions between the bound ligand and the target protein; develop a pharmacophore model based on the target structure. If ligand-bound structures of the target are not available, perform computational analysis to identify major surface cavities in the protein and examine their suitability as binding pockets for drugs. If you happen to work on a disease in which the target protein structure is unknown; find from a protein data bank a homologous protein and perform homology modeling using a suitable web service to obtain 3D model for your target. If the target protein is an enzyme, describe the reaction it catalyzes and identify the transition state either based on the published data (kinetic isotope effect, past computational studies) or your chemical insight. If the reaction is relatively simple (e.g. one-step SN2 displacement), determine the transition state structure using computational approaches that you learned in this class. Locating transition states in more complex reactions (e.g. if a combination of nucleophilic and acid-base catalysis is involved) is more complex; in such cases you can use your chemical intuition to propose a possible transition state structure but you are not required to perform actual calculations. If the target protein is not an enzyme, focus on its mechanism of action. What proteins does it interact with; which are the domain or surface regions involved in these interactions. You can create color-coded 3D representations that highlight different functional parts of the protein. If it is a membrane protein, perform hydropathy analysis and identify transmembrane domains. Find from the literature, which parts of the protein are extracellular, and which parts intracellular. If the target is not an enzyme, you should have the 3D structure of the binding pocket, if not of the complete protein. If there is no structure, use homology modeling to obtain a model. Often, experimental mutagenesis data is very helpful for construction or validation of such homology models. You cannot proceed without having a reasonable model of the binding pocket; in such a case you need to pick another disease/target. You can use software of your choice when performing visualization and modeling of chemical reactions. However, your main goal is to understand how computational methods help us in understanding the binding of ligands and chemical reactivity of substrates; think of computations/visualization methods as aids to generate hypothesis. In this milestone, you are not graded on the effort to generate highly accurate results with