Publications by authors named "J van Voorst"
Identifying physiological ligands is necessary for annotating new protein structures, yet this presents a significant challenge to biologists and pharmaceutical chemists. Here we develop a predictor of cholesterol and cholate binding that works across diverse protein families, extending beyond sequence motif-based prediction. This approach combines SimSite3D site comparison with the detection of conserved interactions in cholesterol/cholate bound crystal structures to define three-dimensional interaction motifs.
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- A conserved bile acid site in cytochrome c oxidase (CcO) affects electron transfer and proton uptake, with diverse amphipathic ligands having been shown to bind to it.
- Current research employs computational methods to identify relevant ligands for this site, including steroids, flavins, and hormones, which interact with specific protein residues involved in binding.
- Experimental assays demonstrate that certain ligands inhibit the function of CcO, indicating a regulatory role and suggesting similarities in inhibition mechanisms between mammalian and bacterial forms of the enzyme.
A software tool and workflow based on distance geometry is presented that can be used to search for local similarity in substructures in a comprehensive database of experimentally derived macromolecular structure. The method does not rely on fold annotation, specific secondary structure assignments, or sequence homology and may be used to locate compound substructures of multiple segments spanning different macromolecules that share a queried backbone geometry. This generalized substructure searching capability is intended to allow users to play an active part in exploring the role specific substructures play in larger protein domains, quaternary assemblies of proteins, and macromolecular complexes of proteins and polynucleotides.
View Article and Find Full Text PDFThe method of conserved core substructure matching (CSM) for the overlay of protein-ligand complexes is described. The method relies upon distance geometry to align structurally similar substructures without regard to sequence similarity onto substructures from a reference protein empirically selected to include key determinants of binding site location and geometry. The error in ligand position is reduced in reoriented ensembles generated with CSM when compared to other overlay methods.
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- The study explores the challenges of identifying high-affinity compounds for drug screening, comparing traditional protein-ligand and ligand-based scoring methods.
- A hybrid approach is proposed, where ligand-based scoring ranks docking results selected by protein-ligand scoring, leading to the discovery of new inhibitors for thrombin during tests on nearly 70,000 compounds.
- The results highlight that different scoring functions significantly influence compound selection, revealing that protein-ligand and ligand-based scoring provide complementary insights into potential drug candidates.