Screen3D: A Novel Fully Flexible High-Throughput Shape-Similarity Search Method

Kalászi, Adrián; Szisz, Dániel; Imre, Gábor; Polgár, Tímea

doi:10.1021/ci400620f

Cited by 39 publications

(25 citation statements)

References 69 publications

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“…A 3D similarity score was generated with the chemistry informatics tool Screen3D [ 57 ] using the atom matching algorithm and allowing the query and template molecules to be flexible. The compounds were categorized into similar groups using the Library MCS hierarchical clustering program Chemaxon (Chemaxon: Budapest H, Library MCS, version 6.0.1,2013).…”

Section: Methodsmentioning

confidence: 99%

Using C. elegans Forward and Reverse Genetics to Identify New Compounds with Anthelmintic Activity

Mathew

Miller

et al. 2016

PLoS Negl Trop Dis

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BackgroundThe lack of new anthelmintic agents is of growing concern because it affects human health and our food supply, as both livestock and plants are affected. Two principal factors contribute to this problem. First, nematode resistance to anthelmintic drugs is increasing worldwide and second, many effective nematicides pose environmental hazards. In this paper we address this problem by deploying a high throughput screening platform for anthelmintic drug discovery using the nematode Caenorhabditis elegans as a surrogate for infectious nematodes. This method offers the possibility of identifying new anthelmintics in a cost-effective and timely manner.Methods/Principal findingsUsing our high throughput screening platform we have identified 14 new potential anthelmintics by screening more than 26,000 compounds from the Chembridge and Maybridge chemical libraries. Using phylogenetic profiling we identified a subset of the 14 compounds as potential anthelmintics based on the relative sensitivity of C. elegans when compared to yeast and mammalian cells in culture. We showed that a subset of these compounds might employ mechanisms distinct from currently used anthelmintics by testing diverse drug resistant strains of C. elegans. One of these newly identified compounds targets mitochondrial complex II, and we used structural analysis of the target to suggest how differential binding of this compound may account for its different effects in nematodes versus mammalian cells.Conclusions/SignificanceThe challenge of anthelmintic drug discovery is exacerbated by several factors; including, 1) the biochemical similarity between host and parasite genomes, 2) the geographic location of parasitic nematodes and 3) the rapid development of resistance. Accordingly, an approach that can screen large compound collections rapidly is required. C. elegans as a surrogate parasite offers the ability to screen compounds rapidly and, equally importantly, with specificity, thus reducing the potential toxicity of these compounds to the host and the environment. We believe this approach will help to replenish the pipeline of potential nematicides.

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Section: Methodsmentioning

confidence: 99%

Using C. elegans Forward and Reverse Genetics to Identify New Compounds with Anthelmintic Activity

Mathew

Miller

et al. 2016

PLoS Negl Trop Dis

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“…[4] Other measures include 2D or 3D descriptors such as MOLPRINT 2D, [5] shape fingerprints, [6] pharmacophore, [7] and 3D structure comparison. [8,9] Using information from existing ligands makes this approach difficult to discover new classes of ligands for the receptor.…”

Section: Introductionmentioning

confidence: 99%

SPOT‐Ligand: Fast and effective structure‐based virtual screening by binding homology search according to ligand and receptor similarity

2016

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Structure-based virtual screening usually involves docking of a library of chemical compounds onto the functional pocket of the target receptor so as to discover novel classes of ligands. However, the overall success rate remains low and screening a large library is computationally intensive. An alternative to this "ab initio" approach is virtual screening by binding homology search. In this approach, potential ligands are predicted based on similar interaction pairs (similarity in receptors and ligands). SPOT-Ligand is an approach that integrates ligand similarity by Tanimoto coefficient and receptor similarity by protein structure alignment program SPalign. The method was found to yield a consistent performance in DUD and DUD-E docking benchmarks even if model structures were employed. It improves over docking methods (DOCK6 and AUTODOCK Vina) and has a performance comparable to or better than other binding-homology methods (FINDsite and PoLi) with higher computational efficiency. The server is available at http://sparks-lab.org. © 2016 Wiley Periodicals, Inc.

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“…Although both are commercial software but an academic license is also available for researchers from academia. Recently, a new tool called Screen3D has recently been reported by ChemAxon for performing shape similarity search [37].…”

Section: Virtual Screeningmentioning

confidence: 99%