Biology subjects

Wellnitz, J.

Publications and source records attributed to Wellnitz, J..

3 recordsLinked to original sources

bioRxiv2025

Open-Source DNA-Encoded Library Package for Design, Decoding, and Analysis: DELi

DNA-encoded library (DEL) technology has become a powerful tool in modern drug discovery. Fully harnessing its potential requires the use of extensive computational methodologies, which are often available only through proprietary software. This restricts accessibility for small teams lacking robust informatics support, hindering the growth of the technology. Here, we present DELi, an open-source DEL informatics platform designed for library design, NGS decoding and calling, and enrichment analysis. DELi supports a simple and easy to understand configuration setup to present a straightforward user interface. To showcase its capabilities, we used DELi to design an in-house custom, benzimidazole-based DEL (UNC DEL006), and performed proof-of-concept selection experiments against Bromodomain-containing Protein 4 (BRD4). The DELi decoding and analysis modules identified top-performing compounds, leading to the off-DNA synthesis of UNC11951, which was confirmed as a nanomolar BRD4 binder via isothermal titration calorimetry (ITC) and differential scanning fluorimetry (DSF). These results demonstrate DELi as an effective tool for DEL design and analysis. Furthermore, its open-source nature will promote ongoing development and contributions from the DEL community to expand its applications and capabilities, making DEL technology more widely accessible. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=94 SRC="FIGDIR/small/640184v3_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@1d4ca88org.highwire.dtl.DTLVardef@13cb4feorg.highwire.dtl.DTLVardef@8ea7ecorg.highwire.dtl.DTLVardef@1b294fc_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2024

Heli-SMACC: Helicase-targeting SMAll Molecule Compound Collection

Helicases have emerged as promising targets for the development of antiviral drugs; however, the family remains largely undrugged. To support the focused development of viral helicase inhibitors we identified, collected, and integrated all chemogenomics data for all available helicases from the ChEMBL database. After thoroughly curating and enriching the data with relevant annotations we have created a derivative database of helicase inhibitors which we dubbed Heli-SMACC (Helicase-targeting SMAll Molecule Compound Collection). The current version of Heli-SMACC contains 20,432 bioactivity entries for viral, human, and bacterial helicases. We have selected 30 compounds with promising viral helicase activity and tested them in a SARS-CoV-2 NSP13 ATPase assay. Twelve compounds demonstrated ATPase inhibition and a consistent dose-response curve. The Heli-SMACC database may serve as a reference for virologists and medicinal chemists working on the development of novel helicase inhibitors. Heli-SMACC is publicly available at https://smacc.mml.unc.edu. HighlightsO_LIWe created a curated Helicase-Targeting SMAll Molecule Compound Collection (Heli-SMACC). C_LIO_LIHeli-SMACC covers 29 human, viral, and bacterial helicases. C_LIO_LITwelve of thirty selected compounds demonstrated inhibitory activity in a SARS-CoV-2 NSP13 ATPase Assay. C_LIO_LIHeli-SMACC is freely available online at https://smacc.mml.unc.edu. C_LI TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=125 SRC="FIGDIR/small/602122v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@8e098forg.highwire.dtl.DTLVardef@115cb2borg.highwire.dtl.DTLVardef@1cd9da3org.highwire.dtl.DTLVardef@2870a6_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2024

Synthesis of 5-Benzylamino and 5-Alkylamino-substituted Pyrimidoquinoline Derivatives as CSNK2A Inhibitors with Antiviral Activity

A series of 5-benzylamine-substituted pyrimido[4,5-c]quinoline derivatives of the CSNK2A chemical probe SGC-CK2-2 were synthesized with the goal of improving kinase inhibitor cellular potency and antiviral phenotypic activity while maintaining aqueous solubility. Among the range of analogs, those bearing electron-withdrawing (4c and 4g) or donating (4f) substituents on the benzyl ring as well as introduction of non-aromatic groups such as the cyclohexylmethyl (4t) were shown to maintain CSNK2A activity. The CSNK2A activity was also retained with N-methylation of SGC-CK2-2, but -methyl substitution of the benzyl substituent led to a 10-fold reduction in potency. CSNK2A inhibition potency was restored with indene-based compound 4af, with activity residing in the S-enantiomer (4ag). Analogs with the highest CSNK2A potency showed good activity for inhibition of Mouse Hepatitis Virus (MHV) replication. Conformational analysis indicated that analogs with the best CSNK2A inhibition (4t, 4ac, and 4af) exhibited smaller differences between their ground state conformation and their predicted binding pose. Analogs with reduced activity (4ad, 4ae, and 4ai) required more substantial conformational changes from their ground state within the CSNK2A protein pocket.

cell biology↗