Biology subjects

Glinca, S.

Publications and source records attributed to Glinca, S..

2 recordsLinked to original sources

bioRxiv2025

Natural Product-Like Fragments Unlock Novel Chemotypes for a Kinase Target - Exploring Options beyond the Flatland

In this study we utilized a high-performance soaking system of protein kinase A (PKA) to perform a crystallographic screening of a natural product-like fragment library. We resolved 36 fragment-bound structures, corresponding to a hit rate of 41%. Nine fragments bound within the ATP site, nine peripherally, and 18 interacted with both the ATP and peripheral sites. One fragment binds to the same site as the approved allosteric kinase inhibitor asciminib, while another induces an unexpected conformational change. Systematic database mining revealed that both the fragments and their natural product parents have not been previously associated with PKA or kinase activity. A scaffold/chemotype analysis further underscored their novelty. Cheminformatics analyses confirmed that these fragments occupy a distinct chemical space, enriched in saturation, spatial complexity and molecular three-dimensional character compared to kinase binders from reference datasets. These properties have previously been linked to increased selectivity, reduced CYP450 inhibition, and higher overall clinical success rates. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/659015v4_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1643255org.highwire.dtl.DTLVardef@124a28eorg.highwire.dtl.DTLVardef@2c4033org.highwire.dtl.DTLVardef@12ae4c5_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2024

Protonation effects in protein-ligand complexes - a case study of endothiapepsin and pepstatin A with computational and experimental methods

1Protonation states serve as an essential molecular recognition motif for biological processes. Their correct consideration is key to successful drug design campaigns, since chemoinformatic tools usually deal with default protonation states of ligands and proteins and miss atypical protonation states. The protonation pattern for the Endothiapepsin/PepstatinA (EP/pepA) complex is investigated using different dry lab and wet lab techniques. ITC experiments revealed an uptake of more than one mole of protons upon pepA binding to EP. Since these experiments were performed at physiological conditions (and not at pH=4 at which a large variety of crystal structures is available), a novel crystal structure at pH=7.6 was determined. This crystal structure showed that only modest structural changes occur upon increasing the pH value. This lead to computational studies to reveal the exact location of the protonation event. Both computational studies could reveal a significant pKa shift resulting in non-default protonation state and that the catalytic dyad is responsible for the uptake of protons. This study shows that assessing protonation states for two separate systems (protein and ligand) might result in the incorrect assignment of protonation states and hence incorrect calculation of binding energy.

molecular biology↗