Computer Aided Drug Design ——Combinatorial...
Transcript of Computer Aided Drug Design ——Combinatorial...
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Computer Aided Drug Design
——Combinatorial library
Qin Xuhttp://cbb.sjtu.edu.cn/~qinxu/CADD.htm
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Course Outline• Introduction and Case Study• Drug Targets
– Sequence analysis– Protein structure prediction– Molecular simulation
• Molecular Docking• Drug Design
– QSAR– Pharmacophore– Structure based drug design
• Database screening• De novo Drug Design• Combinatorial library
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Importance of combinatorial library
• Combinatorial chemistry – Limits of natural products– solid phase synthesis (Merrifield, JACS 1963)– Mixture of large number of compounds (104~106)
in single chemical synthetic process• Virtual molecular library
– Construct molecular library much easier– Optimize molecular library
• High-throughput CADD– QSAR– Pharmacophore– Molecular docking
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Virtual combinatorial library • Fragment screening (分子片段枚举)
• RECAP (分子片段化与重组)
– RECAP analysis– RECAP synthesis
• BREED(配体繁殖)
– Crossover by Genetic algorithm– superposition
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Terms for combinatorial library
Functional group
R-group
Leaving group
Attachment point
Scaffold
Reagent
Reactive atoms
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Fragment screening
• Molecular scaffold– Quinazoline(喹唑啉)
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Fragment screening
• R-group– -CH2-(2-thienyl-))(甲基2噻吩)
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Fragment Enumeration• Screening attachment point A0 on A1->A4• Combinatorial molecules
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RECAP • RECAP analysis
– Generate fragments from source molecules• Extend SMILES
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RECAP analysis
• Ether (C-C-O-C-C)– [OH;ether]– [CH3;ether]
• Isopropyl ether– [OH;ether]– [CH3;ether]C– [CH3;ether]CC
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RECAP synthesis• Reconstruct molecules by
fragments from RECAP analysis– Atom environment– Reaction rules– Attachment points– Databases from RECAP analysis
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• Crossover by Genetic algorithm
BREED
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BREED - Ligand-based design• Crossover points defined by all
superimposed bond pairs
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BREED - Structure-based designWith target protein structure provided, the aligned input
structures are assumed to define the binding pocket.Protein/ligand refinement can be performed for each new structures. 1) Find all residues within a specified distance of the input structures. The atoms in these residues will be treated explicitly and the remainder ignored.2) Side-chain flexibility can be included using a user-specified force constant. If used, small backbone-atom displacements are permitted to reduce strain energies.3) A multi-step minimization process is used with decreasing tether strengths and increasing scope to remove steric clashes and then minimize the protein/ligand complex.4) MM/GBVI (Generalized Born / Volume Integral) energies of the protein/ligand pair are calculated as a score. The RMSD of the ligand heavy atoms is calculated as a goodness-of-fit metric.
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An example of Fragment Enumeration by MOE
Scaffold
Pyrazolone(吡唑啉酮 )
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R-group database
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• DBV|Entry|Select Invalid R-Group Entries– Molecule field: Clipped X-R– Atom Name: A0– Apply
• DBV|Entry|Invert Entry Selection– Select Clipped X-R– Save as…
Get rid of unclipped groups
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Generate Combinatorial library by fragment screening
• QuaSAR-CombiGen– Enumerative Combinatorial library Generation
• QuaSAR-CombiDesign– Selects reagents to optimize diversity in
product space• QuaSAR-CombiReagent
– Selects reagents to optimize functional properties of the products
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Generate Combinatorial library
• QuaSAR-CombiGen– Gmp_scaffold.mdb
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R-group libraries – gmp_r*.mdb
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QuaSAR-CombiGen
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gmp_library.mdbGenerate library
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Reduce Combinatorial libraryQuaSAR-CombiDesign
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Further optimization• QuaSAR-CombiReagent
– Selects reagents to optimize functional properties of the products
– Based on 2D/3D QSAR model, FP models, PH4 models
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Further optimization• QuaSAR-CombiReagent
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Possible models2D or 3D QSAR models
Fingerprint (FP) models
Pharmacophore (Ph4) Query
Above combined
Gmp.binary.fit (A binary QSAR) model
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R-group libraries with predicted activities based on the selected modela*.qcrsel_gmp_r*.mdb
Scaffold libraryqcrsel_c.mdb
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Sort R-groups by predicted activities
Select Top N groups
Save into new databasesqcrsel_gmp_r*.mdb
Repeat slide 24 to generate new libraries
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An example of RECAP analysis and
synthesis by MOE
Source molecules databasecnpd_structures.mdb
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Library of fragmentscnpd_structures_recap.mdb
RECAP synthesis
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recapsynth.mdb
New molecules from RECAP synthesis
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An example of BREED by MOE
Source molecules 10 thrombin inhibitors
ttf_10.mdb
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A simple wayOnly based on structures of ligands
With no knowledge about target structure
Ligand-based design
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New molecules generated by BREED
breed_output.mdb
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Pdb1ets.ent
Delete original ligand
Add Hydrogens
Structure-based designWith a target structure provided
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Load the 10 inhibitors into the binding site
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New molecules generated by BREED
breed_output2.mdb
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Examine the ligands in the binding site
Select the ligand with lowest MM/GBVI
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Examine a ligand in the binding site