Scaffold-hopping potential of ligand-based similarity concepts.
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Ligands↗
Biomedical subjects
Steffen Renner
Publications and source records attributed to Steffen Renner.
A pseudo-ligand approach to virtual screening.
A virtual screening method is presented that is grounded on a receptor-derived pharmacophore model termed "virtual ligand" or "pseudo-ligand". The model represents an idealized constellation of potential ligand sites that interact with residues of the binding pocket. For rapid virtual screening of compound libraries the potential pharmacophore points of the virtual ligand are encoded as an alignment-free correlation vector, avoiding spatial alignment of pharmacophore features between the pharmacophore query (i.e., the virtual ligand) and the candidate molecule. The method was successfully applied to retrieving factor Xa inhibitors from a Ugi three-component combinatorial library, and yielded high enrichment of actives in a retrospective search for cyclooxygenase-2 (COX-2) inhibitors. The approach provides a concept for "de-orphanizing" potential drug targets and identifying ligands for hitherto unexplored or allosteric binding pockets.
Antithrombin III↗
New allosteric modulators of metabotropic glutamate receptor 5 (mGluR5) found by ligand-based virtual screening.
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Allosteric Site↗
New inhibitors of the Tat-TAR RNA interaction found with a "fuzzy" pharmacophore model.
TAR RNA is a potential target for AIDS therapy. Ligand-based virtual screening was performed to retrieve novel scaffolds for RNA-binding molecules capable of inhibiting the Tat-TAR interaction, which is essential for HIV replication. We used a "fuzzy" pharmacophore approach (SQUID) and an alignment-free pharmacophore method (CATS3D) to carry out virtual screening of a vendor database of small molecules and to perform "scaffold-hopping". A small subset of 19 candidate molecules were experimentally tested for TAR RNA binding in a fluorescence resonance energy transfer (FRET) assay. Both methods retrieved molecules that exhibited activities comparable to those of the reference molecules acetylpromazine and chlorpromazine, with the best molecule showing ten times better binding behavior (IC50 = 46 microM). The hits had molecular scaffolds different from those of the reference molecules.
Acepromazine↗
Fuzzy pharmacophore models from molecular alignments for correlation-vector-based virtual screening.
A pharmacophore-based approach for compiling focused screening libraries is presented. It integrates information from three-dimensional molecular alignments into correlation vector-based database screening. The pharmacophore model is represented by a number of spheres of Gaussian-distributed feature densities. Different degrees of "fuzziness" can be introduced to influence the model's resolution. Transformation of this pharmacophore representation into a correlation vector results in a vector of feature probabilities which can be utilized for rapid virtual screening of compound databases or virtual libraries. The approach was validated by retrospective screening for cyclooxygenase 2 (COX-2) and thrombin ligands. A variety of models with different degrees of fuzziness were calculated and tested for both classes of molecules. Best performance was obtained with pharmacophore models reflecting an intermediate degree of fuzziness, yielding an enrichment factor of up to 39 for the first 1% of the ranked database. Appropriately weighted fuzzy pharmacophore models performed better in retrospective screening than similarity searching using only a single query molecule. The new pharmacophore method was shown to complement existing approaches.
Crystallography, X-Ray↗
Comparison of correlation vector methods for ligand-based similarity searching.
Correlation vector methods were tested for their usefulness in ligand-based virtual screening. Three molecular descriptors--two based on potential pharmacophore points and one on partial atom charges--and three similarity measures--the Manhattan distance, the Euclidian distance and the Tanimoto coefficient--were compared. The alignment-free descriptors seem to be particularly applicable when a course-grain filtering of data sets is required in combination with a high execution speed. Significant enrichment of actives was obtained by retrospective analysis. The cumulative percentages for all three descriptors allow for the retrieval of up to 78% of the active molecules in the first five percent of the reference database. Different descriptors retrieved only weakly overlapping sets of active molecules among the top-ranking compounds. If a single similarity index is to be used, the Manhattan distance seems to be particularly applicable. Generally, none of the three different descriptors tested in this study clearly outperformed the others. The suitability of a descriptor critically depends on the ligand-receptor interaction under investigation. For ligand-based similarity searching it is recommended to exploit several descriptors in parallel.
Algorithms↗
Impact of conformational flexibility on three-dimensional similarity searching using correlation vectors.
Many three-dimensional (3D) virtual screening concepts, like automated docking or pharmacophore searching, rely on the calculation of a "bioactive" or "receptor-relevant" conformation of a molecule to assess its biological activity. We investigated the dependence of the presence of conformations near the "bioactive" conformation on three-dimensional similarity searching with pharmacophore-based correlation vectors (CATS3D approach). Cocrystal structures of 11 target classes served as queries for virtual screening of a database of annotated ligands. Different numbers of conformations were calculated. Single 3D structures were obtained using the 3D structure generator CORINA and conformational ensembles by the conformation generation program ROTATE. This approach was able to reproduce conformations for high resolution cocrystal structures. For virtual screening we found that using only the CORINA-generated single conformation already resulted in a significant enrichment of isofunctional molecules having the same biological property profile. This observation was also made for ligand classes with many rotatable bonds. Although more similar conformations were considered to be more similar in the CATS3D description, the impact of using multiple conformations on the enrichment of actives was not as high as expected. CATS3D provides an alignment-free three-dimensional virtual screening approach that is less dependent on the presence of conformations which are close to the "bioactive" conformation of a molecule compared to methods that rely on an explicit three-dimensional alignment of molecules.
Algorithms↗