Difference between revisions of "2010 AMS-535 Fall"

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(Course Participants, Topics, References, and Schedule)
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1. [http://rizzo.ams.sunysb.edu/~rizzo/StonyBrook/teaching/AMS532_AMS535_AMS536/References/Shoichet002.pdf Huang, N.; et al., Benchmarking Sets for Molecular Docking. ''J. Med. Chem.'' '''2006''', ''49(23)'', 6789-6801]
1. [http://rizzo.ams.sunysb.edu/~rizzo/StonyBrook/teaching/AMS532_AMS535_AMS536/References/Shoichet002.pdf Huang, N.; et al., Benchmarking Sets for Molecular Docking. ''J. Med. Chem.'' '''2006''', ''49(23)'', 6789-6801]
2. [http://rizzo.ams.sunysb.edu/~rizzo/StonyBrook/teaching/AMS532_AMS535_AMS536/References/Deng001.pdf Deng, Z; et al., Knowledge-Based Design of Target-Focused Libraries Using Protein-Ligand Interaction Constraints. ''J. Med. Chem.'' '''2006''', ''49'', 490-500]
2. [http://rizzo.ams.sunysb.edu/~rizzo/StonyBrook/teaching/AMS532_AMS535_AMS536/References/Deng001.pdf Deng, Z; et al., Structural Interaction Fingerprint (SIFt): A Novel Method for Analyzing Three-Dimensional Protein-Ligand Binding Interactions. ''J. Med. Chem.'' '''2004''', ''47'', 337-344]

Revision as of 14:21, 20 October 2010

Past Announcements

Current Announcements

  • Posted on 09/07/2010 by Lingling
  1. The PPT for Wednesday's class is available online now.
  2. The presentation schedule is posted. Further modification is needed.
  3. Everyone in the class should be getting an email from me about the presentation schedule. For those who didn't fill in the contact sheet in the first two classes, please email me and let me know your email address. Do email me as well if you don't get my email.
  • Posted on 09/07/2010 by Lingling
  1. I updated the presentation schedule and it's available online. Note that this is still not the final version so don't start preparing for your talk yet.
  2. Everyone in the class should be getting my email tonight about the update of the schedule. If not, that means I don't have your correct email address and please come to see me after Monday's class.
  • Posted on 09/23/2010 by Lingling
  1. Quiz I will be held on Monday in class. It will be thirty-minute closed book quiz. The talk on 09/20 will not be covered in this quiz.
  2. The 20 amino acid side chain structure chart is available as the 2nd reference for the class of 09/13.
  3. The students will start to give presentations from next Wednesday's class. The PPT presentation should be approximately thirty minutes long. Presenters please be prepared for your topics. And PPT for the presentation and 3 associated questions (1 easy, 1 medium, 1 hard) need to be submitted to the TA by the day of your talk.
  • Posted on 10/06/2010 by Lingling
  1. The average score for quiz I is 17.13 out of 25. If you need any help with the problems in the quiz, feel free to make an appointment with me and discuss about them.
  2. Quiz II will be held on 10/11, next Monday. The problems will cover the materials we discussed in class and in the ppt notes. Also, everyone in the class should read the 1st reference paper assigned for each topic.
  3. Students who presented should email me the three quiz questions (one simple, one medium and one hard).
  • Posted on 10/18/2010 by Lingling
  1. The average score for quiz II is 17.29 out of 24. We are eliminating question 6 from the total score as most people get confused by this question. If you need any help with the problems in the quiz, feel free to make an appointment with me and discuss about them.
  2. Students who presented should email me the three quiz questions (one simple, one medium and one hard).
  • Posted on 10/19/2010 by Lingling
  1. The notes for 10/11 to 10/18's classes have been posted. The next quiz is next Wednesday. Please be prepared.

Example Quiz/Exam Questions from Prior Semesters


Course Participants, Topics, References, and Schedule

Speaker and Presentation
Primary Reference
Secondary Reference
2010.08.30 Mon
  • Organizational Meeting
2010.09.01 Wed


  • Drug Discovery
  1. Introduction, history, irrational vs. rational
  2. Viral Target Examples
Rizzo, R.

1. Jorgensen, W.L., The many roles of computation in drug discovery. Science 2004, 303, 1813-8

2. Kuntz, I. D., Structure-based strategies for drug design and discovery. Science 1992, 257, 1078-1082

2010.09.06 Mon
  • No Class: Labor Day
2010.09.08 Wed
  • Chemistry Review
  1. Molecular structure, bonding, graphical representations
  2. Functionality, properties of organic molecules
Class ends at 5:00PM
Rizzo, R.
2010.09.13 Mon
  • Biomolecular Structure
  1. Lipids, carbohydrates
  2. Nucleic acids, proteins
Rizzo, R.
structures of the 20 amino acid side chains
2010.09.15 Wed
  • Molecular Interactions and Recognition
  1. Electrostastics, VDW interactions, hydrophobic effect, molecular recognition (binding energy)
  2. Inhibitors types: allosteric, transition state, covalent vs non-covalent, selective, competitive
Rizzo, R.
2010.09.20 Mon Class in diff location and time
*CHE-607 Modern Drug Design and Discovery: Computational Biology Lectures Rizzo, R.

For today only we will merge with Professor Ojima's "Modern Drug Design and Discovery" class.


Chemistry Department Room 410, 3:20PM - 5:20PM
2010.09.22 Wed
  • Intro. to Methods in 3-D Structure Determination
  1. Crystallography, NMR
  2. Structure Quality, PDB in detail
Rizzo, R.
2010.09.27 Mon
Quiz Prior Section I


  • Classical Force Fields
  1. All-atom Molecular Mechanics

Guest Lecture

Balius, T.

1. Mackerell, A. D., Jr., Empirical force fields for biological macromolecules: overview and issues. J. Comput. Chem. 2004, 25, 1584-604

1. van Gunsteren, W. F.; et al., Biomolecular modeling: Goals, problems, perspectives. Angew. Chem. Int. Ed. Engl. 2006, 45, 4064-92

2010.09.29 Wed
  • Force Field Development
  1. OPLS
  2. AMBER

1. Akter, R.

2. Cao, Y.

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

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

2010.10.04 Mon
  • Explicit Solvent Models
  1. Water models (TIP3P, TIP4P, SPC)
  2. Condensed-phase calculations (DGhydration)

1. Chen, J.

2. Conte, M.

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

2010.10.06 Wed
  • Continuum Solvent Models
  1. Generalized Born Surface Area (GBSA)
  2. Poisson-Boltzmann Surface Area (PBSA)

1. Efaplomatides, C.

2. Fochtman, B.

1. Still, W. C.; et al., Semianalytical Treatment of Solvation for Molecular Mechanics and Dynamics. J. Am. Chem. Soc 1990, 112, 6127-6129

2. Sitkoff, D.; et al., Accurate Calculation of Hydration Free Energies Using Macroscopic Solvent Models. J. Phys. Chem. 1994, 98, 1978-1988

2010.10.11 Mon
Quiz Prior Section II


  • Molecular Conformation
  1. Small molecules, peptides, relative energy, minimization methods

1. Gardin, J.

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

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

2010.10.13 Wed
  • Primary Sampling Methods for Computer Simulations
  1. Molecular dynamics (MD)
  2. Monte Carlo (MC)

1. Maringano, D.

2. Yao, Y

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

2. Metropolis, N.;et al., Equation of State Calculations by Fast Computing Machines. The Journal of Chemical Physics 1953, 21, 1087-1092

2010.10.18 Mon
  • Predicting Protein Structure I.
  1. Ab initio prediction (protein-folding)
  2. Example Trp-cage

1. Grinshpun, B.

2. Hancewicz, J.

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

1-2. Daggett, V.; Fersht, A., The present view of the mechanism of protein folding. Nat. Rev. Mol. Cell Biol. 2003, 4, 497-502

2010.10.20 Wed
  • Predicting Protein Structure II.
  1. Comparative (homology) modeling
  2. Case studies (CASP)

1. Jee, J.

2. Jin, X.

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

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

2010.10.25 Mon
  • Enhanced Sampling Techniques
  1. Simulated annealing
  2. Protein Design

Guest Lecture

Au, L.

1. Brunger, A. T.;Adams, P. D., Molecular dynamics applied to X-ray structure refinement. Acc. Chem. Res. 2002, 35, 404-12

2. Street, A. G.; Mayo, S. L., Computational protein design. Structure. 1999, 7, 105-9

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. Lippow, S. M.; Tidor, B., Progress in computational protein design. Curr. Opin. Biotechnol. 2007, 18, 305-311

2010.10.27 Wed
Quiz Prior Section III


  • Docking I.
  1. Introduction to DOCK

Guest Lecture

Mukherjee, S.

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

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

2010.11.01 Mon
  • Discovery Methods I.
  1. Hotspot probes (GRID)
  2. COMFA

1. Lee, S.

2. Lei, L.

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

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

2010.11.03 Wed
  • Discovery Methods II.
  1. Pharmacaphores in drug design
  2. De nova design

1. Ashiru-Balogun, J.

2. Li, M.

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

2010.11.08 Mon
  • Docking II.
  1. Test Sets (binding modes)
  2. Test Sets (virtual screening)

Guest Lecture

Mukherjee, S.

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

1. The CCDC/Astex Test Set

2. ZINC - A free database of commercially-available compounds for virtual screening

2010.11.10 Wed
  • Docking III.
  1. Enrichment and Rescoring

Guest Lecture Balius, T.

1. Huang, N.; et al., Benchmarking Sets for Molecular Docking. J. Med. Chem. 2006, 49(23), 6789-6801

2. Deng, Z; et al., Structural Interaction Fingerprint (SIFt): A Novel Method for Analyzing Three-Dimensional Protein-Ligand Binding Interactions. J. Med. Chem. 2004, 47, 337-344

2010.11.15 Mon
Quiz Prior Section IV


  • Free Energy Perturbation (FEP)
  1. Thermolysin with two ligands

1. Li, Z.

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

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

2010.11.17 Wed
  • Thermodynamic Integration, MM-PB/GBSA
  1. H5N1 Avian influenza N1-PVR
  2. Intro to Molecular Mechanics Poisson-Boltzmann / Generalized Born Surface Area Methods

1. Liao, J.

2. Liu, J.

1. Lawrenz, M.; et al., Independent-Trajectories Thermodynamic-Integration Free-Energy Changes for Biomolecular Systems: Determinants of H5N1 Avian Influenza Virus Neuraminidase Inhibition by Peramivir. J. Chem. Theory Comput. 2009, 5, 1106-1116

2. 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

2010.11.22 Mon
  • Case study
  1. TI and MM-PBSA
  2. TI and MM-GBSA

1. Liu, Y.

2. Messina, D.

1. Kollman, P. A.; Gouda, H.;Kuntz, I. D.; Case, D. A.; Free Energy Calculations for Theophylline Binding to an RNA Aptamer: Comparison of MM-PBSA and Thermodynamic Integration Methods. Biopolymers. 2003, 68, 16-34

2. Cai, Y.; Schiffer, C. A.; Decomposing the Energetic Impact of Drug Resistant Mutations in HIV-1 Protease on Binding DRV. J. Chem. Theory Comput. 2010, 6, 1358-1368

2010.11.24 Wed
  • No Class: Following a Friday schedule
2010.11.29 Mon
  • MM-GBSA case studies
  1. EGFR
  2. HIVgp41

1. Spaqnuolo, L.

2. Van Wart, T.

1. Balius, T.; Rizzo, R. C.; Quantitative Prediction of Fold Resistance for Inhibitors of EGFR. Biochemistry 2009, 48, 8435-8448

2. 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

2010.12.01 Wed
  • Linear Response
  1. Intro to Linear Response (LR method)
  2. Inhibition of protein kinases (Extended LR method)

1. Yang, R.

2. Hambardzhieva, E.

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. Tominaga, Y.; Jorgensen, W. L.; General model for estimation of the inhibition of protein kinases using Monte Carlo simulations. J. Med. Chem. 2004, 47, 2534-2549

2010.12.06 Mon
  • Properties of Known Drugs
  1. Lipinski Rule of Five
  2. ADME prediction

1. Yerramilli, V.

2. Yu, W.

1. 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

2. Hou, T. J.; Xu, X. J.; ADME evaluation in drug discovery. J. Mol. Model, 2002, 8, 337-349

1. Lipinski, C. A., Chris Lipinski discusses life and chemistry after the Rule of Five. Drug. Discov. Today 2003, 8, 12-6

2. Hou, T. J.; Xu, X. J.; AMDE Evaluation in drug discovery 3. Modeling blood-brain barrier partitioning using simple molecular descriptors. J. Chem. Inf. Comput. Sci., 2003, 43, 2137-2152

2010.12.08 Wed
  • Properties of Known Drugs and Protein Structure Prediction III.
  1. Molecular Scaffolds (frameworks) and functionality (side-chains)
  2. TBA

1. TBA

2. TBA.

1. Bemis, G. W.; Murcko, M. A., The properties of known drugs. 1. Molecular frameworks. J. Med. Chem. 1996, 39, 2887-93

1. Bemis, G. W.; Murcko, M. A., Properties of known drugs. 2. Side chains. J. Med. Chem. 1999, 42, 5095-9

2. TBA

2. TBA

2010.12.13 Mon

Unless otherwise noted the Final will be given in our regular class room.