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Tripos Bookshelf  >  QSAR  >  QSAR Tutorials  >  CoMFA Tutorial

2.4 CoMFA Tutorial

• Preface
• Setting Up
• Creating the Molecular Spreadsheet
• Adding CoMFA Fields
• Performing Statistical Analysis
• Analyzing the CoMFA Results
• Closing the Spreadsheet
• Final Notes
• Practice Exercises

2.4.1 Preface

The following tutorial illustrates the use of Comparative Molecular Field Analysis (CoMFA^TM). You will use CoMFA to determine the structure-activity relationship between a series of steroid compounds and their testosterone binding globulin affinity. A major objective when working with a quantitative structure-activity relationship (QSAR) is to be able to accurately predict the activity of untested compounds.

The binding affinity of a series of steroids to human testosterone-binding globulins (TBG) does not involve bond-making or bond-breaking reactions. However, it does appear to depend on three-dimensional aspects of the steroids.

Although the exact receptor is unknown, it is possible to infer the receptor properties by finding important commonalities of the most active steroids. The CoMFA method proves to be appropriate for such problems. The resulting explanation, or CoMFA model, provides a numerical estimate of TBG activity as well as a qualitative graphical view of the most important three-dimensional aspects of the problem.

The CoMFA study actually begins with the selection of the three-dimensional conformation for each steroid compound, using the building and minimization tools in SYBYL. Both steric bulk and electrostatic potential fields are used to understand the binding behavior, so charges are computed. You must also choose a way to align the steroid compounds atop each other in a way relevant to how they bind. For the steroids, which have a common rigid ring system, SYBYL's fitting capability is used on several atoms along the common rings to align the compounds.

This tutorial takes over at the point where the steroids have all been oriented properly, placed in a molecular database, and ready to use for CoMFA. The molecules, their TBG activity measurements, and the field energies are placed in a Molecular Spreadsheet.

The QSAR tools are applied to find the best predictive model of the system, using crossvalidation. The results are viewed as regions surrounding the steroids where steric bulk or electrostatic potential most strongly affect the TBG activity. Applying the quantitative model of the TBG you can predict the activity of a different steroid.

After completing this tutorial, you will be able to:

• Create a Spreadsheet for QSAR studies which includes CoMFA columns.
• Check for a predictively useful result by use of crossvalidation.
• Display the spatial distribution of important steric and electrostatic properties affecting the activity.
• Predict which proposed compounds will be most active.

Before starting this tutorial, you should be familiar with the basic behavior of the Molecular Spreadsheet, interactive graphs, and the Small Molecule Building tutorial.