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J Chem Inf Model. 2019 Jul 22;59(7):3177-3190. doi: 10.1021/acs.jcim.9b00380. Epub 2019 Jul 1.

Influence of the Structural Accuracy of Homology Models on Their Applicability to Docking-Based Virtual Screening: The β2 Adrenergic Receptor as a Case Study.

Abstract

How accurate do structures of the β2 adrenergic receptor (β2AR) need to be to effectively serve as platforms for docking-based virtual screening campaigns? To answer this research question, here, we targeted through controlled virtual screening experiments 23 homology models of the β2AR endowed with different levels of structural accuracy. Subsequently, we studied the correlation between virtual screening performance and structural accuracy of the targeted models. Moreover, we studied the correlation between virtual screening performance and template/target receptor sequence identity. Our study demonstrates that docking-based virtual screening campaigns targeting homology models of the β2AR, in the majority of the cases, yielded results that exceeded random expectations in terms of area under the receiver operating characteristic curve (ROC AUC). Moreover, with the most effective scoring method, over one-third and one-quarter of the models yielded results that exceeded random expectation also in terms of enrichment factors (EF1, EF5, and EF10) and BEDROC (α = 160.9), respectively. Not surprisingly, we found a detectable linear correlation between virtual screening performance and structural accuracy of the ligand-binding cavity. We also found a detectable linear correlation between virtual screening performance and structural accuracy of the second extracellular loop (EL2). Finally, our data indicate that, although there is no detectable linear correlation between virtual screening performance and template/β2AR sequence identity, models built on the basis of templates that show high sequence identity with the β2AR, especially within the ligand-biding cavity, performed consistently well. Conversely, models with lower sequence identity displayed performance levels that ranged from very good to random, with no apparent correlation with the sequence identity itself.

PMID:
31257873
DOI:
10.1021/acs.jcim.9b00380

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