Date
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Topic
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Speaker and Presentation
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Primary Reference
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Secondary Reference
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2008.09.03 Wed
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2008.09.08 Mon
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SECTION I: DRUG DISCOVERY AND BIOMOLECULAR STRUCTURE
- Introduction, history, irrational vs. rational
- Viral Target Examples
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Rizzo, R.
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1-2. Jorgensen, W. L., The many roles of computation in drug discovery. Science 2004, 303, 1813-8
1-2. Kuntz, I. D., Structure-based strategies for drug design and discovery. Science 1992, 257, 1078-1082
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2008.09.10 Wed
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- Molecular structure, bonding, graphical representations
- Functionality, properties of organic molecules
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Rizzo, R.
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presentation
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-
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2008.09.15 Mon
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- Lipids, carbohydrates
- Nucleic acids, proteins
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Rizzo, R.
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presentation
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2008.09.17 Wed
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- Molecular Interactions and Recognition
- Electrostastics, VDW interactions, hydrophobic effect, molecular recognition (binding energy)
- Inhibitors types: allosteric, transition state, covalent vs non-covalent, selective, competitive
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Rizzo, R.
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presentation
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2008.09.22 Mon
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2008.09.24 Wed
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- Intro. to Methods in 3-D Structure Determination
- Crystallography, NMR
- Structure Quality, PDB in detail
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Rizzo, R.
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presentation
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2008.09.29 Mon class ends at 5:00
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Quiz Prior Section I
SECTION II: MOLECULAR MODELING
- All-atom Molecular Mechanics
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1. Goyal, R.
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1. Mackerell, A. D., Jr., Empirical force fields for biological macromolecules: overview and issues. J. Comput. Chem. 2004, 25, 1584-604
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1. van Gunsteren, W. F.; et al., Biomolecular modeling: Goals, problems, perspectives. Angew. Chem. Int. Ed. Engl. 2006, 45, 4064-92
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2008.10.01 Wed
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2008.10.06 Mon class in diff location
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- CHE-607 Modern Drug Design and Discovery: Computational Biology Lectures
- TBA
- TBA
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1. Simmerling, C.
2. Rizzo, R.
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NOTE:
For today only we will merge with Professor Ojima's "Modern Drug Design and Discovery" class.
CLASS ROOM CHANGE:
Chemistry Department Room 410
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2008.10.08 Wed class ends at 5:00
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- OPLS
- AMBER
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1. Au, L.
2. Holden, P.
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1. Jorgensen, W. L.; et al., Development and Testing of the OPLS All-Atom Force Field on Conformational Energetics and Properties of Organic Liquids. J. Am. Chem. Soc. 1996, 118, 11225-11236
2. Cornell, W. D.; et al., A Second Generation Force Field For the Simulation of Proteins, Nucleic Acids, and Organic Molecules. J. Am. Chem. Soc. 1995, 117, 5179-5197
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1. Jorgensen, W. L.; et al., The Opls Potential Functions For Proteins - Energy Minimizations For Crystals of Cyclic-Peptides and Crambin. J. Am. Chem. Soc. 1988, 110, 1657-1671
2. Bayly, C. I.; et al., A Well-Behaved Electrostatic Potential Based Method Using Charge Restraints For Deriving Atomic Charges - the RESP Model. J. Phys. Chem. 1993, 97, 10269-10280
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2008.10.13 Mon
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- Water models (TIP3P, TIP4P, SPC)
- Condensed-phase calculations (DGhydration)
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1. Brody, D.
2. Gettings, J.
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1. Jorgensen, W. L.; et al., Comparison of Simple Potential Functions for Simulating Liquid Water. J. Chem. Phys. 1983, 79, 926-935
2. Jorgensen, W. L.; et al., Monte Carlo Simulation of Differences in Free Energies of Hydration. J. Chem. Phys. 1985, 83, 3050-3054
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2008.10.15 Wed
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- Generalized Born Surface Area (GBSA)
- Poisson-Boltzmann Surface Area (PBSA) vs GBSA
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1. Lebarron, J.
2. Rizzo, R.
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1. Still, W. C.; et al., Semianalytical Treatment of Solvation for Molecular Mechanics and Dynamics. J. Am. Chem. Soc 1990, 112, 6127-6129
2. Rizzo, R. C. ; Aynechi, T.; Case, D. A.; Kuntz, I. D. Estimation of Absolute Free Energies of Hydration Using Continuum Methods: Accuracy of Partial Charge Models and Optimization of Nonpolar Contributions. J. Chem. Theory Comput. 2006, 2, 128-139
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2008.10.20 Mon
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Quiz Prior Section II
SECTION III: SAMPLING METHODS
- Small molecules, peptides, relative energy, minimization methods
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1. Lee, J.
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1. Howard, A. E.; Kollman, P. A., An analysis of current methodologies for conformational searching of complex molecules. J. Med. Chem. 1988, 31, 1669-75
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1. NIH Online Molecular Modeling Guide
1. Section 4 (PAGES 22-27) Colby College Molecular Mechanics Tutorial Introduction, 2004, Shattuck, T.W., Colby College
1. Holloway, M. K., A priori prediction of ligand affinity by energy minimization. Perspect. Drug Discov. Design 1998, 9-11, 63-84
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2008.10.22 Wed
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- Primary Sampling Methods for Computer Simulations
- Molecular dynamics (MD)
- Monte Carlo (MC)
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1. Liao, W.
2. Liverpool, R.
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1. Karplus, M.; Petsko, G. A., Molecular dynamics simulations in biology. Nature 1990, 347, 631-9
2. Metropolis Monte Carlo Simulation Tutorial, LearningFromTheWeb.net, Accessed Oct 2008, Luke, B.
2. Jorgensen, W. L.; TiradoRives, J., Monte Carlo vs Molecular Dynamics for Conformational Sampling. J. Phys. Chem. 1996, 100, 14508-14513
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2. Metropolis, N.; et al., Equation of State Calculations by Fast Computing Machines. The Journal of Chemical Physics 1953, 21, 1087-1092
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2008.10.27 Mon
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- Predicting Protein Structure I.
- Ab initio prediction (protein-folding)
- Example Trp-cage
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1. Lu, Y.
2. Mulundi, P.
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1. Dill, K. A.; Chan, H. S., From Levinthal to pathways to funnels. Nat. Struct. Biol. 1997, 4, 10-19
2. Simmerling, C.; et al., All-atom structure prediction and folding simulations of a stable protein. J. Am. Chem. Soc. 2002, 124, 11258-9
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1-2. Daggett, V.; Fersht, A., The present view of the mechanism of protein folding. Nat. Rev. Mol. Cell Biol. 2003, 4, 497-502
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2008.10.29 Wed
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- Predicting Protein Structure II.
- Comparative (homology) modeling
- Case studies (CASP)
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1. Mwai, A.
2. Ray, N.
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1. Marti-Renom, M. A.; et al., Comparative protein structure modeling of genes and genomes. Annu. Rev. Biophys. Biomol. Struct. 2000, 29, 291-325
2. Moult, J., A decade of CASP: progress, bottlenecks and prognosis in protein structure prediction. Curr. Opin. Struct. Biol. 2005, 15, 285-9
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1. Fiser, A.; et al., Evolution and physics in comparative protein structure modeling. Acc. Chem. Res. 2002, 35, 413-21
2. Kryshtafovych, A.; et al., Progress over the first decade of CASP experiments. Proteins 2005, 61 Suppl 7, 225-36
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2008.11.03 Mon
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- Enhanced Sampling Techniques
- Simulated annealing
- Replica Exchange
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1. Schaefer, K.
2. Seitz, J.
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1. Brunger, A. T.; Adams, P. D., Molecular dynamics applied to X-ray structure refinement. Acc. Chem. Res. 2002, 35, 404-12
2. Sugita, Y.; Miyashita, N.; Yoda, T.; Ikeguchi, M.; Toyoshima, C., Structural Changes in the Cytoplasmic Domain of Phospholamban by Phosphorylation at Ser16: A Molecular Dynamics Study. Biochemistry 2006, 45, 11752-11761
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1. Adams, P. D.; et al., Extending the limits of molecular replacement through combined simulated annealing and maximum-likelihood refinement. Acta Crystallogr D Biol Crystallogr 1999, 55, 181-90
2. Sugita, Y.; Okamoto, Y., Replica-exchange molecular dynamics method for protein folding. Chem. Phys. Lett. 1999, 314, 141-151
2. Lei, H.; Duan, Y., Improved sampling methods for molecular simulation. Curr Opin Struct Biol 2007, 17, 187-91
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2008.11.05 Wed
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Quiz Prior Section III
SECTION IV: LEAD DISCOVERY
- Introduction to DOCK
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Guest Lecture
1. Mukherjee, S.
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1. Ewing, T. J.; et al., DOCK 4.0: search strategies for automated molecular docking of flexible molecule databases. J. Comput. Aided Mol. Des. 2001, 15, 411-28
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1. Moustakas, D. T.; et al., Development and Validation of a Modular, Extensible Docking program: DOCK 5. J. Comput. Aided Mol. Des. 2006, 20, 601-619
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2008.11.10 Mon
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- Test Sets (binding modes)
- Test Sets (virtual screening)
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Guest Lecture
1. Mukherjee, S.
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1. Nissink, J. W. M.; et al., A new test set for validating predictions of protein-ligand interaction. Prot. Struct. Funct. Genetics 2002, 49, 457-471
2. Irwin, J. J.; Shoichet, B. K., ZINC--a free database of commercially available compounds for virtual screening. J. Chem. Inf. Model. 2005, 45, 177-82
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1. The CCDC/Astex Test Set
2. ZINC - A free database of commercially-available compounds for virtual screening
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2008.11.12 Wed
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- Hotspot probes (GRID)
- COMFA
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1. Shang, Y.
2. Tan, L.
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1. Goodford, P. J., A computational procedure for determining energetically favorable binding sites on biologically important macromolecules. J. Med. Chem. 1985, 28, 849-57
2. Kubinyi, H., Encyclopedia of Computational Chemistry, Databases and Expert Systems Section, John Wiley & Sons, Ltd. 1998
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1. Cramer, R. D.; Patterson, D. E.; Bunce, J. D., Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. J. Am. Chem. Soc., 1988, 110, 5959-5967
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2008.11.17 Mon
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- Pharmacaphores in drug design
- De nova design
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1. Wang, H.
2. Wu, J.
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1. Chang, C.; et al., Pharmacophore-based discovery of ligands for drug transporters. Advanced Drug Delivery Reviews 2006, 58, 1431-1450
2. Pegg, S. C.; Haresco, J. J.; Kuntz, I. D., A genetic algorithm for structure-based de novo design. J Comput Aided Mol Des 2001, 15, 911-33
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2008.11.19 Wed
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- Discovery Methods Applications
- Human Carbonic Anhydrase
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1. Yang, M.
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1. Gruneberg, S.; Stubbs, M. T.; Klebe, G., Successful virtual screening for novel inhibitors of human carbonic anhydrase: strategy and experimental confirmation. J. Med. Chem. 2002, 45, 3588-602
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1. Cramer, R. D.; Patterson, D. E.; Bunce, J. D., Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. J. Am. Chem. Soc., 1988, 110, 5959-5967
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2008.11.24 Mon
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Quiz Prior Section IV
SECTION V: LEAD REFINEMENT
- Free Energy Perturbation (FEP)
- Thermolysin with 2 ligands
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1. Goyal, R.
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1. Bash, P. A.; Singh, U. C.; Brown, F. K.; Langridge, R.; Kollman, P. A., Calculation of the relative change in binding free energy of a protein-inhibitor complex. Science 1987, 235, 574-6
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1. Jorgensen, W. L., Free Energy Calculations: A Breakthrough for Modeling Organic Chemistry in Solution. Accounts Chem. Res. 1989, 22, 184-189
1. Kollman, P., Free Energy Calculations: Applications to Chemical and Biochemical Phenomena. Chem. Rev. 1993, 93, 2395-2417
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2008.11.26 Wed
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- Intro to Molecular Mechanics Poisson-Boltzmann / Generalized Born Surface Area Methods
- MM-PBSA Validation Study
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Guest Lecture
1. Huang, Y.
2. Balius, T.
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1. Kollman, P. A.; Massova, I.; Reyes, C.; Kuhn, B.; Huo, S. H.; Chong, L.; Lee, M.; Lee, T.; Duan, Y.; Wang, W.; Donini, O.; Cieplak, P.; Srinivasan, J.; Case, D. A.; Cheatham, T. E., Calculating structures and free energies of complex molecules: Combining molecular mechanics and continuum models. Accounts Chem. Res. 2000, 33, 889-897
2. Kuhn, B.; Gerber, P.; Schulz-Gasch, T.; Stahl, M., Validation and use of the MM-PBSA approach for drug discovery. J. Med. Chem. 2005, 48, 4040-4048
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2008.12.01 Mon
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- HIVgp41
- influenza
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1. Rizzo, R.
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1. Strockbine, B.; Rizzo, R. C., Binding of Anti-fusion Peptides with HIVgp41 from Molecular Dynamics Simulations: Quantitative Correlation with Experiment. Prot. Struct. Funct. Bioinformatics 2007, 63, 630-642
2. Chachra, R.; Rizzo, R. C. Origins of Resistance Conferred by the R292K Neuraminidase Mutation via Molecular Dynamics and Free Energy Calculations. J. Chem. Theory Comput. 2008, 4, 1526-1540
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2008.12.03 Wed
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- Intro to Linear Response (LR method)
- Inhibition of protein kinases (Extended LR method)
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1. Rizzo, R.
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1. Aqvist, J.; Mowbray, S. L., Sugar recognition by a glucose/galactose receptor. Evaluation of binding energetics from molecular dynamics simulations. J Biol Chem 1995, 270, 9978-81
2. Rizzo, R. C.; Tirado-Rives, J.; Jorgensen, W. L., Estimation of Binding Affinities for HEPT and Nevirapine Analogues with HIV-1 Reverse Transcriptase via Monte Carlo Simulations. J. Med. Chem. 2001, 44, 145-154
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2008.12.08 Mon
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- Properties of Known Drugs
- Estrogen Receptor
- Molecular Scaffolds (frameworks) and functionality (side-chains)
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Guest Lecture
1. Yang, J.
2. McGillick, B.
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1. Waszkowycz, B.; Perkins, T. D. J.; Sykes, R. A.; Li, J., Large-scale virtual screening for discovering leads in the postgenomic era. IBM Systems Journal 2001, 40, 360-376
2. Bemis, G. W.; Murcko, M. A., The properties of known drugs. 1. Molecular frameworks. J. Med. Chem. 1996, 39, 2887-93
2. Bemis, G. W.; Murcko, M. A., Properties of known drugs. 2. Side chains. J. Med. Chem. 1999, 42, 5095-9
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2. Lipinski, C. A., Chris Lipinski discusses life and chemistry after the Rule of Five. Drug. Discov. Today 2003, 8, 12-6
2. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J., Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug. Deliv. Rev. 2001, 46, 3-26
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2008.12.10 Wed
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- Working in a Pharmaceutical Company
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Guest Lecture
Dr. Elizabeth Buck
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1. OSI Pharmaceuticals
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2008.12.15 Mon
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- No Class: University Correction Day
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2008.12.17 Wed
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FINAL EXAM
WED
5:00 - 7:30 PM
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NOTE:
Unless otherwise noted the Final will be given in our regular class room.
FINAL EXAM IS CUMULATIVE
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