Challenging the Gold Standard for 3D-QSAR: Template CoMFA Versus X-ray Alignment

Overview

Journal J Comput Aided Mol Des

Publisher Springer

Specialties Biomedical Engineering
Molecular Biology

Date 2014 Jun 18

PMID 24934658

Citations 8

Authors

Bernd Wendt

Richard D Cramer

Affiliations

Soon will be listed here.

Abstract

X-ray-based alignments of bioactive compounds are commonly used to correlate structural changes with changes in potencies, ultimately leading to three-dimensional quantitative structure-activity relationships such as CoMFA or CoMSIA models that can provide further guidance for the design of new compounds. We have analyzed data sets where the alignment of the compounds is entirely based on experimentally derived ligand poses from X-ray-crystallography. We developed CoMFA and CoMSIA models from these X-ray-determined receptor-bound conformations and compared the results with models generated from ligand-centric Template CoMFA, finding that the fluctuations in the positions and conformations of compounds dominate X-ray-based alignments can yield poorer predictions than those from the self-consistent template CoMFA alignments. Also, when there exist multiple different binding modes, structural interpretation in terms of binding site constraints can often be simpler with template-based alignments than with X-ray-based alignments.

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