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