Biology subjects

Sacher, J. R.

Publications and source records attributed to Sacher, J. R..

3 recordsLinked to original sources

bioRxiv2025

Unlocking Scalable Ligand Residence Time Predictions with Koffee Unbinding Kinetics Simulations

A great number of drug discovery programs fail due to poor in vivo efficacy and ADMET liabilities. On- and off-target ligand residence times can act as important drivers of these problems. While modern experimental techniques have made measuring compound kinetics data more routine, there is a lack of accurate, high-throughput simulation techniques to guide compound prioritization by residence time. In this work, we introduce Koffee Unbinding Kinetics as a solution to the hitherto unanswered problem of scalable ligand-protein residence time prediction. By bypassing conventional approaches based on molecular dynamics simulations, Koffee Unbinding Kinetics performs physics-based residence time screening at the atomistic level in {approx} 1 GPU minute per complex using inexpensive hardware, a speed-up of at least 3 - 5 orders of magnitude compared to current state-of-the-art simulation approaches. Koffee Unbinding Kinetics can enhance compound selection to mitigate costly future program failures by adding fast, predictive residence time simulations to early-stage computational drug discovery pipelines. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/686759v3_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@120d5dcorg.highwire.dtl.DTLVardef@b86b67org.highwire.dtl.DTLVardef@193554forg.highwire.dtl.DTLVardef@1c5c6c1_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2021

Discovery of small molecule pathway regulators by image profile matching

Identifying chemical regulators of biological pathways is a time-consuming bottleneck in developing therapeutics and research compounds. Typically, thousands to millions of candidate small molecules are tested in target-based biochemical screens or phenotypic cell-based screens, both expensive experiments customized to each disease. Here, our uncustomized, virtual profile-based screening approach instead identifies compounds that match to pathways based on phenotypic information in public cell image data, created using the Cell Painting assay. Our straightforward correlation-based computational strategy retrospectively uncovered the expected, known small molecule regulators for 32% of positive-control gene queries. In prospective, discovery mode, we efficiently identified new compounds related to three query genes, and validated them in subsequent gene-relevant assays, including compounds that phenocopy or pheno-oppose YAP1 overexpression and kill a Yap1-dependent sarcoma cell line. This image profile-based approach could replace many customized labor- and resource-intensive screens and accelerate the discovery of biologically and therapeutically useful compounds. One sentence summaryIf a genetic perturbation impacts cell morphology, a computational query can reveal compounds whose morphology "matches".

bioinformatics↗

bioRxiv2020

Multimodal small-molecule screening for human prion protein binders

Prion disease is a rapidly progressive neurodegenerative disorder caused by misfolding and aggregation of the prion protein (PrP), and there are currently no therapeutic options. PrP ligands could theoretically antagonize prion formation by protecting the native protein from misfolding or by targeting it for degradation, but no validated small-molecule binders have been discovered to date. We deployed a variety of screening methods in an effort to discover binders of PrP, including 19F-observed and saturation transfer difference (STD) nuclear magnetic resonance (NMR) spectroscopy, differential scanning fluorimetry (DSF), DNA-encoded library selection, and in silico screening. A single benzimidazole compound was confirmed in concentration-response, but affinity was very weak (Kd > 1 mM), and it could not be advanced further. The exceptionally low hit rate observed here suggests that PrP is a difficult target for small-molecule binders. While orthogonal binder discovery methods could yield high affinity compounds, non-small-molecule modalities may offer independent paths forward against prion disease.

biochemistry↗