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bioRxiv · 10.1101/2024.07.17.603966

Identifying Artifacts from Large Library Docking

Wu, Y.·Liu, F.·Glenn, I.·Fonseca-Valencia, K.·Paris, L.·Xiong, Y.·Jerome, S. V.·Brooks, C. L.·Shoichet, B. K.
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Abstract

While large library docking has discovered potent ligands for multiple targets, as the libraries have grown, the very top of the hit-lists can become populated with artifacts that cheat our scoring functions. Though these cheating molecules are rare, they become ever-more dominant with library growth. Here, we investigate rescoring top-ranked molecules from docking screens with orthogonal methods to identify these artifacts, exploring implicit solvent models and absolute binding free energy perturbation (AB-FEP) as cross-filters. In retrospective studies, this approach deprioritized high-ranking non-binders for nine targets while leaving true ligands relatively unaffected. We tested the method prospectively against results from large library docking AmpC {beta}-lactamase. From the very top of the docking hit lists, we prioritized 128 molecules for synthesis and experimental testing, a mixture of 39 molecules that rescoring flagged as likely cheaters and another 89 that were plausible true actives. None of the 39 predicted cheating compounds inhibited AmpC up to 200{micro}M in enzyme assays, while 57% of the 89 plausible true actives did do so, with 19 of them inhibiting the enzyme with apparent Ki values better than 50{micro}M. As our libraries continue to grow, a strategy of catching docking artifacts by rescoring with orthogonal methods may find wide use in the field. Graphical TOC Entry O_FIG O_LINKSMALLFIG WIDTH=166 HEIGHT=200 SRC="FIGDIR/small/603966v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@c2f1a5org.highwire.dtl.DTLVardef@86bc58org.highwire.dtl.DTLVardef@1b739c7org.highwire.dtl.DTLVardef@325b93_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Wu, Y., Liu, F., Glenn, I., Fonseca-Valencia, K., Paris, L., Xiong, Y., Jerome, S. V., Brooks, C. L., Shoichet, B. K.. 2024-07-18. Identifying Artifacts from Large Library Docking. https://doi.org/10.1101/2024.07.17.603966

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