Combi-Chem

Contents

Release 4.5, June 2000

1. Introduction

Overview of Cerius2 combinatorial chemistry objectives

Rational design of combinatorial libraries

Role of Cerius2 combinatorial chemistry software suite

How to use this documentation set

Contents and organization

Who should use this documentation set

Additional information

Typographical conventions

2. Start-up and Configuration

Running Cerius2

Prerequisites

Starting the program

Daylight setup

Setting environment variables

Testing licenses

Cerius2 setup

Oracle setup

Setting environment variables

MDL ISIS setup

Setting environment variables

3. Tutorials

3a. Library building

Building a benzodiazepine library

3b. Importing libraries into Cerius2

Importing the benzodiazepine library

Importing compounds from WDI

3c. Library analysis and visualization

Visualizing compounds in descriptor space

Using principal component analysis

Using multi-dimensional scaling

3D Pharmacophore Fingerprinting (C2·3DKeys)

Fingerprinting and clustering (C2·LibEngine)

3d. Compound selection procedures

Identification of outliers

Selecting diverse compounds

Cluster-based selections

Distance-based selections

Cell-based selections

Selecting similar compounds

3e. C2·LibProfile Penalty based Diversity and Similarity Selection

Product Diversity based on property ranges

Diversity based on profiling product properties of an existing dataset

Diversity Constrained by Reagent Properties

Advanced binning and factorial design

3f. Library comparison and augmentation

Comparing library diversity

Distance-based library augmentation

Hole identification and hole filling

Distance histogram - library comparison

Distance histogram - library augmentation

3g. Combinatorial design

Diverse combinatorial design

Focused combinatorial design

3h. Importing and working with BDF files

3i. Addendum: Data and demonstration files

Conclusion

4. Combinatorial Chemistry Methodologies

4a. Introduction

Accessing the combinatorial chemistry modules

Planning the diversity experiments

Reagent selection

Parallel synthesis

Combinatorial synthesis

Lead discovery

Optimization

4b. Import/export procedures

Import/export compounds from SMILES

Import smiles

Export smiles

SMARTS Search

Tcl commands for SMARTS substructure searching

SMARTS table derivations

More information about Daylight

Limitations

Import/Export libraries from MDL RG files

Import RG files

Export RG files

Importing data from Oracle tables

Logging in to the Oracle server (Oracle Logon)

Setting up the import process (Column Selection)

Specification of Oracle Table (Available Tables)

Specification of Oracle Columns (Table Columns)

4c. Analog Builder

How the analog builder works

Outline of general procedure

Specific methodology for building analogs

Creating a core structure

Accessing the analog-building tools

Defining R group attachment sites

Specifying substituent groups

Double-linked and Symmetrical R-groups

Bridging R-group special case: the null-fragment:

Symmetrical R-groups

Multiply bonded R-groups

Fragment extraction from database searches

Reading all required structures from a library

Importing and exporting fragments

Generating analogs

Setting preferences

4d. Library analysis techniques

Choosing molecular diversity descriptors

Using molecular diversity descriptors

Standard descriptor sets

3D field descriptors

Fingerprint descriptors

Catalyst descriptors

Daylight descriptors

Kier and Hall E-state descriptors

Calculating molecular diversity descriptors

Descriptor calculation for combinatorial libraries (C2·LibEngine)

Loading molecular diversity descriptors

Managing molecular diversity descriptors

Fast calculation of 2D descriptors

Comparison of standard and fast calculation

Performing fast descriptor calculation

ISIS keys and Daylight fingerprints

3D Pharmacaphore fingerprints (3DKeys)

Creating feature (FEA) file from a BDB file

Creating 3D fingerprint (3PF, 4PF) file from a feature (FEA) file

Adding a 3D fingerprint column to the study table

Selecting similarity coefficients and displaying pharmacophores

Pharmacophore visualization in Cerius2

File conversion utilities

Creating a catalyst query from single pharmacophore

Creating a 3D Fingerprint file (.3pf, .4pf) from a single pharmacophore

Merging binary fingerprint files

Loading binary fingerprint files into the study table

Statistical analyses and data-mining techniques

Analysis of property distribution

Analysis of descriptor correlation

Advanced binning

Binning

Saving and loading binnings

Analysis

Handling large libraries

Handling structures

File-based system

Handling descriptors

4e. Library visualization

Visualization of compounds in descriptor space

Principal component analysis

Factor analysis

Cluster analysis

Dendrogram-study table Interaction

Multidimensional scaling

4f. Compound selection procedures

Identification of outliers

Selecting diverse compounds

Cluster-based selections

Distance-based selections

Cell-based selections

Optimizing existing selections

Selecting similar models

Selecting restrained models

Selecting random compounds

Compound selection preferences

4g. Diversity under restraints (C2·LibProfile)

Specifying property ranges

Accessing the tools

Using property ranges

The .prn file

Specifying property profiles

Accessing the tools

Using Property Profiles

Example .ppf file

Specifying reagent penalty restraints

Accessing the tools

The reagents table

Example reagent table

The supplier table

Example suppliers table

Reagents penalty function

Using reagent penalties

Calculate Penalties

List Status

Clear All Penalties

4h. Library comparison and augmentation

Introduction

Library definition

Comparing library diversity

Distance-based library augmentation

Hole identification and hole filling

Distance histogram library comparison

4i. Combinatorial design

Introduction

Diverse combinatorial design

Focused combinatorial design

5. Theory

Definition of metric spaces

Molecular diversity descriptors

Introduction

Graph-theoretic descriptors

Topological descriptors that do not distinguish heteroatoms

Example

Definition:

Topological descriptors that distinguish heteroatoms

Information-theoretic descriptors

Information of atomic composition index (IAC-mean, IAC-total)

Information indices based on the A-matrix

Example

Information indices based on the D-matrix

Information indices based on the E-matrix and the ED-matrix

Multigraph information content indices (IC, BIC, CIC, SIC)

Descriptors based on projections of the molecular surface (shadow indices)

Descriptors based on partial charges mapped on surface area

2D and 3D fingerprints metrics

Cosine-coefficient diversity

Data-reduction and -visualization techniques

Principal component analysis

Descriptor and component scaling

Descriptor scaling

Component scaling

Factor analysis

Multi-dimensional scaling

Diversity metric functions

Distance-based functions

Cell-based functions

Stochastic optimization procedures

Functional form of the reagents penalty function

Conclusions

A. References