3D-Quantitative Structure Activity Relationships of Biphenyl Carboxylic Acid MMP-3 Inhibitors: Exploring Automated Docking as Alignment Method
✍ Scribed by Muegge, Ingo ;Podlogar, Brent L.
- Publisher
- John Wiley and Sons
- Year
- 2001
- Tongue
- English
- Weight
- 182 KB
- Volume
- 20
- Category
- Article
- ISSN
- 1611-020X
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✦ Synopsis
A series of CoMFA models have been derived from docking-based and atom-based alignments. The statistics of these approaches has been compared to determine whether a docking approach can be employed as an automated alignment tool for the development of 3D-QSAR models. Using a well-characterized training set of 51 biphenyl carboxylic acid MMP-3 inhibitors, the docking-based alignment provided by a DOCK4yPMFscoring protocol has yielded statistically significant, crossvalidated CoMFA models comparable to those derived with a traditional atom-based alignment technique. Field fit minimization has been applied to refine the atom-based and docking-based alignments. The refinement appears to be beneficial for the docking-based approach. For the atom-based alignment, however, field-fit refinement has not resulted in improved CoMFA models. The statistically best CoMFA model has been created by the atombased alignment that has been found, however, to be inconsistent with the stromelysin crystal structure. The docking alignment refined by field-fit alignment has resulted in a final alignment that is consistent with the crystal structure and only slightly statistically inferior to the atom-based aligned CoMFA model. The results show the ability of an automated dockingyfield-fit alignment technique to provide self-consistent CoMFA alignments.