Prospective Assessment of Virtual Screening Heuristics Derived Using a Novel Fusion Score.

Dante A Pertusi,Gregory O'Donnell, Michelle F Homsher, Kelli Solly, Amita Patel, Shannon L Stahler,Daniel Riley,Michael F Finley, Eleftheria N Finger,Gregory C Adam,Juncai Meng, David J Bell,Paul D Zuck, Edward M Hudak, Michael J Weber,Jennifer E Nothstein, Louis Locco, Carissa Quinn,Adam Amoss,Brian Squadroni, Michelle Hartnett,Mee Ra Heo, Tara White, S Alex May, Evelyn Boots, Kenneth Roberts, Patrick Cocchiarella, Alex Wolicki,Anthony Kreamer,Peter S Kutchukian,Anne Mai Wassermann,Victor N Uebele,Meir Glick,Andrew Rusinko,J Christopher Culberson

SLAS DISCOVERY(2017)

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摘要
High-throughput screening (HTS) is a widespread method in early drug discovery for identifying promising chemical matter that modulates a target or phenotype of interest. Because HTS campaigns involve screening millions of compounds, it is often desirable to initiate screening with a subset of the full collection. Subsequently, virtual screening methods prioritize likely active compounds in the remaining collection in an iterative process. With this approach, orthogonal virtual screening methods are often applied, necessitating the prioritization of hits from different approaches. Here, we introduce a novel method of fusing these prioritizations and benchmark it prospectively on 17 screening campaigns using virtual screening methods in three descriptor spaces. We found that the fusion approach retrieves 15% to 65% more active chemical series than any single machine-learning method and that appropriately weighting contributions of similarity and machine-learning scoring techniques can increase enrichment by 1% to 19%. We also use fusion scoring to evaluate the tradeoff between screening more chemical matter initially in lieu of replicate samples to prevent false-positives and find that the former option leads to the retrieval of more active chemical series. These results represent guidelines that can increase the rate of identification of promising active compounds in future iterative screens.
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关键词
ultra-high-throughput screening,chemoinformatics,computational chemistry,statistical analyses
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