Computer Aided Drug Design. Protein structure prediction. Qin Xu

Transcription

1 Computer Aided Drug Design Protein structure prediction Qin Xu

2 Course Outline Introduction and Case Study Drug Targets Sequence analysis Protein structure prediction Homology modeling with Discovery Studio Model Evaluations Structural databases, structural classification databases, and structural/functional databases of proteins Molecular simulation Drug Design Combinatorial library 3D-QSAR Statistical methods Molecular Docking

3 Tools for Modeling SWISS-MODEL MODEL.html Accelrys Discovery Studio MODELLER MOE HHpred ROBETTA

4 Homology Modeling with Accelrys Discovery Studio Download Free version ery-studio/visualizationdownload.php A full version of Accelrys Discovery Studio 3.5 available on the server of the department ( :9943) Apply for an account first!

5 Accelrys Discovery Studio 3.5 Input the MMP14 sequence New Protein Sequence Window right button open menu, Insert Sequence New Sequence, Select Untitled1,right button open menu, Rename Sequence, change the name to MMP14 Paste the sequence of MMP14

6 Blast Search

7 Blastp Search on NCBI

8 Select templates by score, coverage, identity Three example templates selected

9 The structures of the three templates from PDB database

10 Align and Superimpose the templates

11 Structural comparison of the templates

12 Align target sequence to templates

13 Build Homology Models

14 Verify models by scores

15 Data table Verify models by PDF (Probability density functions)

16 Verify models by Ramachandran Plot

17 Course Outline Introduction and Case Study Drug Targets Sequence analysis Protein structure prediction Homology modeling with Discovery Studio Model Evaluations Structural databases, structural classification databases, and structural/functional databases of proteins Molecular simulation Drug Design Combinatorial library 3D-QSAR Statistical methods Molecular Docking

18 Typical errors in homology modeling Model (thick line) X-ray (thin line) X-ray Model Model X-ray Template (broken line) Errors in Side chain Packing (Trp) Correct alignment Errors due to misalignments Template Errors in the regions without template

19 Evaluations of Protein structure predictions Comparative Assessment of techniques of Protein Structure Prediction (CASP) A Meeting of modeling and other computational approaches for protein structure predictions o CASP1 (1994) CASP2 (1996) CASP3 (1998) CASP4 (2000) CA SP5 (2002) CASP6 (2004) CASP7 (2006) CASP8 (2008) CASP 9 (2010) CASP10 (2012) CASP11 (2014)

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22 Prediction groups

23 Prediction results

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25 Accuracy of predicted models

26 Templates Models

27 Progress of protein structure prediction in CASP GlobalDistanceTest_ TotalScore Kryshtafovych, A. et al. Proteins. S7: ,2005

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30 3D Structural prediction and drug-target interactions Example 1. A homology model for the mmcp-7 and heparin interaction ( Stevens et al, JBC, 1995 )

31 The surface of mmcp-7 A homology model for mmcp-7 (space filling). His residues shown in green. Electrostatic potential for normal mmcp-7. Three positive charged His produce a region with a positive potential for the binding of heparin. ph=5.5 Electrostatic potential for His68->Glu68 mutant. The positive potential is diminished due to the mutation.

32 Structural prediction of TM domains and drug-target interactions Example 2. A comparative model for human A3 adenosine receptor and antagonist interactions (Baraldi et al, J. Med. Chem., 2002 )

33 Course Outline Introduction and Case Study Drug Targets Sequence analysis Protein structure prediction Homology modeling with Discovery Studio Model Evaluations Structural databases, structural classification databases, and structural/functional databases of proteins Molecular simulation Drug Design Combinatorial library 3D-QSAR Statistical methods Molecular Docking