Target Identification of Small Molecules Using Large-Scale CRISPR–Cas Mutagenesis Scanning of Essential Genes

Kwanten, Bert; Neggers, Jasper E.; Daelemans, Dirk

doi:10.1007/978-1-0716-1720-5_3

Cited by 2 publications

(1 citation statement)

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“…Hence, a phenotypic screening is usually paired by a set of studies for determining the mechanism of action, at least for the most promising compounds. Such a challenging task is supported by a rich arsenal of experimental methods, including biochemical affinity analyses [ 8 , 9 ], “omics” profiling [ 10 , 11 , 12 ], and mutational studies [ 13 ]. Furthermore, this task can greatly benefit from computational studies, which become even more necessary when dealing with huge datasets [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Target Prediction by Multiple Virtual Screenings: Analyzing the SARS-CoV-2 Phenotypic Screening by the Docking Simulations Submitted to the MEDIATE Initiative

Gervasoni,

Manelfi,

Adobati

et al. 2023

IJMS

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Phenotypic screenings are usually combined with deconvolution techniques to characterize the mechanism of action for the retrieved hits. These studies can be supported by various computational analyses, although docking simulations are rarely employed. The present study aims to assess if multiple docking calculations can prove successful in target prediction. In detail, the docking simulations submitted to the MEDIATE initiative are utilized to predict the viral targets involved in the hits retrieved by a recently published cytopathic screening. Multiple docking results are combined by the EFO approach to develop target-specific consensus models. The combination of multiple docking simulations enhances the performances of the developed consensus models (average increases in EF1% value of 40% and 25% when combining three and two docking runs, respectively). These models are able to propose reliable targets for about half of the retrieved hits (31 out of 59). Thus, the study emphasizes that docking simulations might be effective in target identification and provide a convincing validation for the collaborative strategies that inspire the MEDIATE initiative. Disappointingly, cross-target and cross-program correlations suggest that common scoring functions are not specific enough for the simulated target.

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