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submitted on 23.10.2019 and posted on 25.10.2019by Maurice Michel, Evert J. Homan, Elisee Wiita, Kia Pedersen, Ingrid Almlöf, Anna-Lena Gustavsson, Thomas Lundbäck, Thomas Helleday, Ulrika Warpman Berglund
Computational chemistry has now been widely accepted as a useful tool for shortening lead times in early drug discovery. When selecting new potential drug targets, it is important to assess the likelihood of finding suitable starting points for lead generation before pursuing costly high-throughput screening campaigns. By exploiting available high-resolution crystal structures, an in silico druggability assessment can facilitate the decision of whether, and in cases where several protein family members exist, which of these to pursue experimentally. Many of the algorithms and software suites commonly applied for in silico druggability assessment are complex, technically challenging and not always user-friendly. Here we applied the intuitive open access servers of DoGSite, FTMap and CryptoSite to comprehensively predict ligand binding pockets, druggability scores and conformationally active regions of the NUDIX protein family. In parallel we analyzed potential ligand binding sites, their druggability and hydrophobic-hydrophilic ratio using Schrödinger’s SiteMap. Then an in silico docking cascade of a subset of the ZINC FragNow library using the Glide docking program was performed to assess identified pockets for large-scale small molecule binding. Subsequently, this initial dual ranking of druggable sites within the NUDIX protein family was benchmarked against experimental hit rates obtained both in-house and by others from traditional biochemical and fragment screening campaigns. The observed correlation suggests that the presented user-friendly workflow of a dual parallel in silico druggability assessment is applicable as a standalone method for decision on target prioritization in future screening campaigns.
Science for Life Laboratory, Karolinska Institute, Department of Oncology and Pathology
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Declaration of Conflict of Interest
TH is listed as an inventor of patents describing NUDT1 and NUDT5 inhibitors. EH is listed as an inventor of a patent describing NUDT1 inhibitors. The patents are fully owned by a non-profit public foundation, the Helleday Foundation, and TH and UWB are member of the foundation board developing inhibitors towards and in the clinic (NCT03036228). TL is an employee of AstraZeneca, but performed all experimental work associated with this publication while at Chemical Biology Consortium Sweden. The remaining authors declare no competing financial interests.