Combination of 2D/3D Ligand-Based Similarity Search in Rapid Virtual Screening from Multimillion Compound Repositories. Selection and Biological Evaluation of Potential PDE4 and PDE5 Inhibitors

Abstract

Rapid in silico selection of target focused libraries from commercial repositories is an attractive and cost effective approach. If structures of active compounds are available rapid 2D similarity search can be performed on multimillion compound databases but the generated library requires further focusing by various 2D/3D chemoinformatics tools. We report here a combination of the 2D approach with a ligand-based 3D method (Screen3D) which applies flexible matching to align reference and target compounds in a dynamic manner and thus to assess their structural and conformational similarity. In the first case study we compared the 2D and 3D similarity scores on an existing dataset derived from the biological evaluation of a PDE5 focused library. Based on the obtained similarity metrices a fusion score was proposed. The fusion score was applied to refine the 2D similarity search in a second case study where we aimed at selecting and evaluating a PDE4B focused library. The application of this fused 2D/3D similarity measure led to an increase OPEN ACCESSMolecules 2014, 19 7009 of the hit rate from 8.5% (1st round, 47% inhibition at 10 µM) to 28.5% (2nd round at 50% inhibition at 10 µM) and the best two hits had 53 nM inhibitory activities.

2D and 3D similarity landscape analysis identifies PARP as a novel off-target for the drug Vatalanib

“…Accurate target prediction can be achieved by combining different measures of chemical similarity based on both chemical structure and molecular shape [ 32 ]. Furthermore it has been shown recently that the combination of a 2D similarity search and a 3D shape/flexibility-based similarity search led to an increased hit rate [ 33 ]. Therefore 3D-similarity of VEGFR and PARP inhibitors was then analysed by a proprietary 3D-superpostion algorithm, which produces reproducible results because of pre-calculated conformers for every compound.…”

Identification of a novel dual-target scaffold for 3CLpro and RdRp proteins of SARS-CoV-2 using 3D-similarity search, molecular docking, molecular dynamics and ADMET evaluation

“…This filtered database has been submitted to a simplepharmacophore based VS (3D-similarity search (Dobi et al, 2014)) workflow as a first step, and obtained molecules from this step have finally used in a VS using molecular docking.…”

“…As there are just few inhibitors known for the two new studied proteins of SARS-CoV-2, here we suggest a simple approach to obtain focused databases for 3CLpro (N3 Cocrystallized ligand) and RdRp SARS-CoV-2 targets based on single ligand pharmacophore, unlike other ligand-based VS methods, the main feature of our approach; is using similarity search in 3D (Dobi et al, 2014); is based on two fitting methods, which could enhance the accuracy, the first one based on overlapping the pharmacophores generated from the candidate structure (B from a database) and the query (reference molecule A), then rank them based on the Root Mean Squared Deviation (RMSD), The formula of RMSD is given by the Equation (1):…”

“…The second one is using T A,B score, which is a similarity between the reference structure, A and database aligned molecules, B are represented by vector, x, of length n with the ith property having the value xi (Sheridan, 2007).The formula of Tanimoto coefficient (Dobi et al, 2014) is given by the Equation (2):…”

Identification of steroid-like natural products as antiplasmodial agents by 2D and 3D similarity-based virtual screening

“…15 2D and 3D similarity-search methods have been successfully employed in parallel or in combination to identify novel compounds for various targets. [16][17][18] This communication reports the findings of a study in which 2D and 3D similarity-based virtual screening approaches were employed to identify fusidic acid-like structurally diverse compounds from an in-house database using fusidic acid as a search query. Selected hit compounds were evaluated in vitro for antiplasmodial activity against the P. falciparum NF54 strain to reveal new active antiplasmodial compounds.…”