Combi-Chem

1       Introduction

This chapter is an introduction to this documentation set Cerius² Combinatorial Chemistry Software Suite. It includes:

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

Drug discovery projects have traditionally required testing hundreds or perhaps thousands of individually synthesized and characterized chemicals; the new techniques of robotic synthesis, combinatorial chemistry, and high-throughput screening (HTS) offer the possibility of rapidly preparing and testing hundreds of thousands or more samples. This increased throughput dramatically increases the probability of finding a lead compound with the proper balance of activity, specificity, safety, bioavailability, and stability to result in a successful new drug. The process involves the tight integration of synthesis and screening methods and can be subdivided into four interconnected activities: (1) library specification, (2) library design and analysis, (3) library data management, and (4) library structure activity relationship (SAR) determination. In many ways, this new process represents a microcosm of discovery efforts within pharmaceutical and agrochemical companies, where powerful analysis capabilities must be closely integrated with flexible project data management and laboratory automation.

Rational design of combinatorial libraries

Medicinal chemists working in drug discovery face questions such as:

• How can I optimize the screening of natural products or existing compounds to find a lead?

• Which analog or modification to a known lead should I make next?

• Which combinatorial library should I screen first?

• Can I screen effectively with a subset of the library?

• Are my libraries diverse or well focused?

• What library should I make or purchase next, to optimize my screening abilities?

• What library should I make or purchase next, to screen around a lead compound?

• C²·QSAR. The Cerius² QSAR module includes a study table control panel: a spreadsheet with knowledge of molecules, including tools to facilitate its use with large data sets. It also includes several molecular descriptors, along with statistical regression techniques.

• C²·Descriptor+. This extension to standard Cerius² descriptors includes Kier and Hall molecular indices and access to ISIS and Daylight topological fingerprints.

• C²·Analog Builder provides combinatorial building abilities with any number of R groups. It also includes SD file import-capabilities and enables core plus R group approaches in QSAR applications.

• C²·Diversity. The Cerius² Diversity module is the core combinatorial chemistry module. It provides access to several diversity/similarity selection techniques, including both distance-based and cell-based approaches.

• C²·LibCompare provides library comparison capabilities. Libraries may be evaluated in terms of diversity or complementarity with regard to a parent library. Libraries may be polled for complementary of follow-up sets of compounds.

• C²·LibSelect incorporates combinatorial design constraints in the elaboration of diverse or focused libraries.

How to use this documentation set

In addition, a table of contents and index are included to help you find specific information.

Contents and organization

• Installation and Configuration provides information about specific procedures for the Cerius² combinatorial chemistry software suite, such as Daylight, Oracle, and ISIS connectivities.

• Tutorials shows you how to use the functionality of the Cerius² Combinatorial Chemistry Software Suite by taking you through specific examples.

• Combinatorial Chemistry Methodologies gives a detailed perspective on how to go about solving specific combinatorial chemistry problems using the Cerius² Combinatorial Chemistry Software Suite.

• Theory presents the theory that is implemented in the Cerius² Combinatorial Chemistry Software Suite.

• References lists the references cited in this documentation set.

You should already be familiar with some aspects of:

• The Cerius² graphical user interface.

• Basic Cerius² facilities for model manipulation.

• Cerius² Modeling Environment -- Describes the integrated set of tools for session management and atomistic modeling that form the core of the Cerius² modeling environment.

• Cerius² Builders -- Discusses the specialized builder modules (Analog Builder, Crystal Builder, Surface Builder, Interface Builder, Polymer Builder, and Amorphous Builder) that can be added to supplement the basic model sketching capabilities provided by the Cerius² modeling environment.

• Cerius² Installation and Administration Guide -- Provides step-by-step instructions for installing and administering Cerius² in your operating environment.

• Cerius² QSAR+ -- Describes QSAR as implemented in Cerius² and how to use it.

• Depending on your needs, the Cerius² guides for other modules such as those for Simulation Tools and the Quantum Chemistry modules, may be useful.

• Text is in normal fonts

• Variables are in italic type.

• Words you enter and text identifying controls in the interface are in bold type.