Post on 16-Aug-2020
Computer Aided Drug Design
——Combinatorial library
Qin Xuhttp://cbb.sjtu.edu.cn/~qinxu/CADD.htm
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
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
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
Terms for combinatorial library
Functional group
R-group
Leaving group
Attachment point
Scaffold
Reagent
Reactive atoms
Fragment screening
• Molecular scaffold– Quinazoline(喹唑啉)
Fragment screening
• R-group– -CH2-(2-thienyl-))(甲基2噻吩)
Fragment Enumeration• Screening attachment point A0 on A1->A4• Combinatorial molecules
RECAP • RECAP analysis
– Generate fragments from source molecules• Extend SMILES
RECAP analysis
• Ether (C-C-O-C-C)– [OH;ether]– [CH3;ether]
• Isopropyl ether– [OH;ether]– [CH3;ether]C– [CH3;ether]CC
RECAP synthesis• Reconstruct molecules by
fragments from RECAP analysis– Atom environment– Reaction rules– Attachment points– Databases from RECAP analysis
• Crossover by Genetic algorithm
BREED
BREED - Ligand-based design• Crossover points defined by all
superimposed bond pairs
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.
An example of Fragment Enumeration by MOE
Scaffold
Pyrazolone(吡唑啉酮 )
R-group database
• 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
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
Generate Combinatorial library
• QuaSAR-CombiGen– Gmp_scaffold.mdb
R-group libraries – gmp_r*.mdb
QuaSAR-CombiGen
gmp_library.mdbGenerate library
Reduce Combinatorial libraryQuaSAR-CombiDesign
Further optimization• QuaSAR-CombiReagent
– Selects reagents to optimize functional properties of the products
– Based on 2D/3D QSAR model, FP models, PH4 models
Further optimization• QuaSAR-CombiReagent
Possible models2D or 3D QSAR models
Fingerprint (FP) models
Pharmacophore (Ph4) Query
Above combined
Gmp.binary.fit (A binary QSAR) model
R-group libraries with predicted activities based on the selected modela*.qcrsel_gmp_r*.mdb
Scaffold libraryqcrsel_c.mdb
Sort R-groups by predicted activities
Select Top N groups
Save into new databasesqcrsel_gmp_r*.mdb
Repeat slide 24 to generate new libraries
An example of RECAP analysis and
synthesis by MOE
Source molecules databasecnpd_structures.mdb
Library of fragmentscnpd_structures_recap.mdb
RECAP synthesis
recapsynth.mdb
New molecules from RECAP synthesis
An example of BREED by MOE
Source molecules 10 thrombin inhibitors
ttf_10.mdb
A simple wayOnly based on structures of ligands
With no knowledge about target structure
Ligand-based design
New molecules generated by BREED
breed_output.mdb
Pdb1ets.ent
Delete original ligand
Add Hydrogens
Structure-based designWith a target structure provided
Load the 10 inhibitors into the binding site
New molecules generated by BREED
breed_output2.mdb
Examine the ligands in the binding site
Select the ligand with lowest MM/GBVI
Examine a ligand in the binding site