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Bioinformatics and Drug Design
Institute of Bioinformatics and Structural Biology,Department of Life Science,National Tsing Hua University
Chao-Sheng Cheng
Watson and Crick, May 1953(From Robert Olby, The Path to the Double Helix, 1974)
1953 DNA1962 1990
2003414
James Watson
http://www.ensembl.org/
http://www.ncbi.nlm.nih.gov/
GeneBank
Ex. Cancer related genes !!
Information ComplexityInformation Complexity
DNA
Bioinformatics
()
?
?
The Size of Cell
What is Cell ?
virtual cell http://www.virtualcell.com/
Virtual Frog Dissectionhttp://www-itg.lbl.gov/Frog/
Cells Life
- Computer training of surgical skills
http://www.cellsalive.com/
http://www.virtualcell.com/
http://www.froguts.com/http://www-itg.lbl.gov/Frog/
http://brc.life.nthu.edu.tw/
http://www.mi.auc.dk/virtualbrain/
(colon cancer)
Search results for query "colon cancer": 17 hits
http://www.ncbi.nlm.nih.gov/
TGFBR2 KNOWN Colon cancer; Colorectal cancer, hereditary nonpolyposis, type 6
MFS2 PHENO Marfan-like connective tissue disorder
MLH1 KNOWN Colorectal cancer, hereditary nonpolyposis, type 2, 114500
PSORS5 PHENO Psoriasis, susceptibility to, 177900
DLEC1 KNOWN Lung cancer, 211980; Esophageal cancer
ACAA1 KNOWN Pseudo-Zellweger syndrome, 261510
DNA RNA
Demonstrate similarity among sequencesIdentify functionally important sitesStructure predictionMolecular phylogenySearch for weak but significant similarity/primer design
Consensus seq.
Conserved region
Seq. ASeq. BSeq. C
Conserved motif
One Seq. with homology to A, B, C
-
HIV-1 Protease Complexed With A Tripeptide Inhibitor
Docking(binding state)
10000~20000
2~32~32~3
2~3
3~4
10~122.0~3.5
Drug Characteristic
Must be safe to use
Must be effective for the intended use
Must be stable (chemically and metabolically)
Must have a good solubility profile
Must be synthetically feasible
Must be novel (patentable)
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Computer Aided Drug Design
Target Structure
Target Structure
Ligand-based approachesLigand-based approaches Structure-based approachesStructure-based approaches
knownunknown
(Pharmacophore + QSAR) (Docking; De novo design)
30
Computer Aided Drug DesignTwo different strategies:
Ligand-based (analog-based) design Relies on a set of known ligands and is particularly valuable if no
structural information about the receptor is available.
Structure-based (target-based) design Usually starts with the structure of a receptor site, such as the active
site in a protein. This structure can be generated from direct experimentation or can
be deduced from experimental structures through homology modeling
31
Definition of a Pharmacophore A pharmacophore can be defined as a specific 3D
arrangement of chemical groups common to active molecules and essential to their biological activities.
32
SAR: Structure-activity relationship
Bioisosteric Replacements
Molecules that are designed by bioisosteric replacements are expected to have similar biological properties.
Programs
Catalyst Sybyl Discovery Studio
34
Computational ligand designTwo different strategies:
Ligand-based (analog-based) design Relies on a set of known ligands and is particularly valuable if no
structural information about the receptor is available.
Structure-based (target-based) design Usually starts with the structure of a receptor site, such as the active
site in a protein. This structure can be generated from direct experimentation or can
be deduced from experimental structures through homology modeling
35
Structure-based (target-based) design
(Krumrine et al., 2003)
* Homology modeling
Homology modeling:software
Modeller: http://salilab.org/modeller/tutorial/ DeepViewer: http://ca.expasy.org/spdbv/text/disclaim.htm What If: http://swift.cmbi.ru.nl/servers/html/index.html Discovery Studio/InsightII
Homology modeling:Web-Service
SWISS-MODEL: http://swissmodel.expasy.org/ What If: http://swift.cmbi.ru.nl/servers/html/index.html CPHmodels 2.0: http://www.cbs.dtu.dk/services/CPHmodels/ PredictProtein: http://www.predictprotein.org/
Quality Check of the protein structure
ProsaII ......... check protein energy Procheck ........ check protein geometric Whatcheck.. check protein geometric
39
Structure-based (target-based) design
(Krumrine et al., 2003)
Dock known chemicals from an in silico database into the receptor target site (database searching or screening). Design of novel compounds to fit into receptor target site
(de novo design).
* Homology modeling
40
Design MethodsDesign Methods
1.1. DockingDocking
2.2. Database searchingDatabase searching
41
Docking is an energy-based operation for exploring the binding modes of two interaction molecules.
Give the 3D structure of a protein target, compuonds can be designed to fit in a cavity, which is called "docking".
The treatment ends when a minimum of energy is obtained for the complex.
Definition of Docking
42
Docking Goal
1. To build the binding model between ligand and protein
2. To clarify the critical residues which involve in ligand binding
3. To engineer the protein by mutagenesis
4. To develop a drug from a compound database
43
Docking Require
Ligand structure
Protein structure
Docking software
Ligand: XK-263
Protein: HIV-1 Protease (1hvr)
Software: AutoDock version 2.4
44
Docking Flowchart
InputInput
OutputOutput
DockingDocking
LimitationLigand structureProtein structure
AutodockDockLudiGramm
Complex structure informationAnalysis ProSall, SWISS PDB ViewerEvaluation
For Input Data:
Protein must be high resolution!
B factors
NMR(Poorly constrained regions)
Ligand StructureChemical drawing
ChemOffice Discovery Studio/InsightII Sybyl ISIS Draw Alchemy2000 The Dundee PRODRG2 Server
Ligand Structure from database Protein Data Bank Zinc database Cambridge Structural Database CrossFire Database/Beilstein, Gmelin, EcoPharm MDL ISIS Database, (Chinese) CCDC/Relibase Protein-Ligand Structure Database National Cancer Institute SoP Computer-Aided Drug Design Center
Protein Structure
Download: Protein Data Bank: http://www.rcsb.org/pdb/home/home.do
Build the model by yourself!!
48
Docking Flowchart
InputInput
OutputOutput
DockingDocking
LimitationLigand structureProtein structure
AutodockDockLudiGramm
Complex structure informationAnalysis ProSall, SWISS PDB ViewerEvaluation
ForcesReceptor and ligand flexibilitySolventBinding mode
Need to consider .
Docking Program Protein-Protein Docking
ZDOCK/RDOCK PatchDOCK DOCK GRAMM Molfit HADDOCK
Protein-Ligand Docking GOLD AutoDOCK DOCK GRAMM Molegro FlexX Discovery Studio
50
Docking Flowchart
InputInput
OutputOutput
DockingDocking
LimitationLigand structureProtein structure
AutodockDockLudiGramm
Complex structure informationAnalysis ProSall, SWISS PDB ViewerEvaluation
For Output Data:
(active sites)
(Geometry)
(potential energy)
Docking Analyses
Molecular visualization Calculation of Binding Energies Score Function
Molecular Visualization
Molecular Visualization
Rasmol Chime SWISS PDB Viewer Discovery Studio/insightII Sybyl Molegro Pymol
MolMol Molscript GRASP Coot O Chimera
Protein Surface Map GRASP MS MSMS Naccess Surfnet Connolly Delphi Dms MolMol PyMol Swiss PDB Viewer Discovery Studio
Structural Alignment1. CE2. Discovery Studio/InsightII3. Swiss PDB Viewer4. MolMol5. Vector Alignment Search Tool (VAST)
Protein volume & cavity size
Voidoo GRASP SWISS PDB Viewer Volume+Access
Interaction - Ligplot
Binding Energy & Kd
MMTSB + charmm or amber SCORE DynFit Discovery Studio
Virtual screening
59
60
2. Database searching 3D Database Searching
In practice the database approach provides an easy way to arrive at leads. It consists of a 3D computerized search of a database of synthesized or naturally occurring compounds and testing them in silico.
The result of this treatment is a list of compounds ranked by a score based on the overall match with the receptor.
61
2. Database searching Databases of Molecules in 3D
Throughout the world there are thousands of chemical suppliers offering more than 3 million of organic molecules.
The advantage of using commercially available molecules in database searching is that they offer a great diversity and can be purchased and tested rapidly.
62
Figure 2. (a) Binding conformations of docked
compounds at the active sites of CatK.
63Compound 38
Figure 3. (a) Plots of pIC50 versus ChemScore
energy for compounds from the training and the test sets.
(b) Proposed interaction model of inhibitor 38 in the active sites of CatK
Figure 3b represents the interaction model of the docked inhibitor 38with CatK, as generated withthe program Ligplot.
Figure 3b represents the interaction model of the docked inhibitor 38with CatK, as generated withthe program Ligplot.
Database Cambridge Structural Database CrossFire Database/Beilstein, Gmelin, EcoPharm MDL ISIS Database, (Chinese) CCDC/Relibase Protein-Ligand Structure Database National Cancer Institute SoP Computer-Aided Drug Design Center Zinc database
64
Virtual Screening Program
DOCK AutoDOCK GOLD Discovery Studio Molegro FlexX
66
Structure-based (target-based) design
(Krumrine et al., 2003)
Dock known chemicals from an in silico database into the receptor target site (database searching or screening). Design of novel compounds to fit into receptor target site
(de novo design).
* Homology modeling
De-Novo design
67
68
3. De-Novo design Automated Construction Approaches
The purpose of construction programs is to discover a new chemical framework that fits to the active site of the target receptor or enzyme.
Some methods are based on an existing moiety and additional fragments are appended by a step-by-step build up procedure.
Other methods consist of assembling novel molecules from pieces that are positioned optimally in favorable regions of the active site.
Program
LigBuilder Ludi
69
70
!
Bioinformatics Center, NTHU