Explicit Diversity Index (EDI):  A Novel Measure for Assessing the Diversity of Compound Databases

Papp, Ákos; Gulyás-Forró, Anna; Gulyás, Zsolt; Dormán, György; Ürge, László; Darvas, Ferenç

doi:10.1021/ci060074f

Cited by 6 publications

(3 citation statements)

References 42 publications

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“…A library of 199,082 compounds of >85% purity at >5 mg amount (available at AMRI Inc., Hungary) was virtually filtered through a set of absorption, distribution, metabolism and excretion, and toxicity (ADME-Tox) filters and ranked according to drug likeness index (Xu and Stevenson, 2000). The selected set of 54,000 compounds was further reduced by applying diversity criteria (Papp et al, 2006), and the resulting library of 18,400 compounds was then screened at 5 μM concentration in a cell-based high-throughput assay with a luciferase readout in cells expressing GFRα1 and RET (Sidorova et al, 2010). Forty-three compounds that induced luciferase response by at least three times above the baseline were then tested in luciferase assay in triplicates in 5 μM concentration to confirm their biological activity.…”

Section: Resultsmentioning

confidence: 99%

A Novel Small Molecule GDNF Receptor RET Agonist, BT13, Promotes Neurite Growth from Sensory Neurons in Vitro and Attenuates Experimental Neuropathy in the Rat

Sidorova

2017

Front. Pharmacol.

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Neuropathic pain caused by nerve damage is a common and severe class of chronic pain. Disease-modifying clinical therapies are needed as current treatments typically provide only symptomatic relief; show varying clinical efficacy; and most have significant adverse effects. One approach is targeting either neurotrophic factors or their receptors that normalize sensory neuron function and stimulate regeneration after nerve damage. Two candidate targets are glial cell line-derived neurotrophic factor (GDNF) and artemin (ARTN), as these GDNF family ligands (GFLs) show efficacy in animal models of neuropathic pain (Boucher et al., 2000; Gardell et al., 2003; Wang et al., 2008, 2014). As these protein ligands have poor drug-like properties and are expensive to produce for clinical use, we screened 18,400 drug-like compounds to develop small molecules that act similarly to GFLs (GDNF mimetics). This screening identified BT13 as a compound that selectively targeted GFL receptor RET to activate downstream signaling cascades. BT13 was similar to NGF and ARTN in selectively promoting neurite outgrowth from the peptidergic class of adult sensory neurons in culture, but was opposite to ARTN in causing neurite elongation without affecting initiation. When administered after spinal nerve ligation in a rat model of neuropathic pain, 20 and 25 mg/kg of BT13 decreased mechanical hypersensitivity and normalized expression of sensory neuron markers in dorsal root ganglia. In control rats, BT13 had no effect on baseline mechanical or thermal sensitivity, motor coordination, or weight gain. Thus, small molecule BT13 selectively activates RET and offers opportunities for developing novel disease-modifying medications to treat neuropathic pain.

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Section: Resultsmentioning

confidence: 99%

A Novel Small Molecule GDNF Receptor RET Agonist, BT13, Promotes Neurite Growth from Sensory Neurons in Vitro and Attenuates Experimental Neuropathy in the Rat

Sidorova

2017

Front. Pharmacol.

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“…Clustering is usually based on the Maximum Common Substructure search [65] algorithm. Scaffold analysis could also be combined with the simple chemical diversity selection and a combined index could reflect both (EDI, Explicit Diversity Index) [66]. For better and more efficient performance the 2D/3D similarity selection methods can be combined.…”

Section: Filtering the Initial 2d Similarity Search Resultsmentioning

confidence: 99%

Rapid Identification of Potential Drug Candidates from Multi-Million Compounds’ Repositories. Combination of 2D Similarity Search with 3D Ligand/Structure Based Methods and In Vitro Screening

Szilágyi¹,

Flachner²,

Hajdú³

et al. 2021

Molecules

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Rapid in silico selection of target focused libraries from commercial repositories is an attractive and cost-effective approach in early drug discovery. If structures of active compounds are available, rapid 2D similarity search can be performed on multimillion compounds’ databases. This approach can be combined with physico-chemical parameter and diversity filtering, bioisosteric replacements, and fragment-based approaches for performing a first round biological screening. Our objectives were to investigate the combination of 2D similarity search with various 3D ligand and structure-based methods for hit expansion and validation, in order to increase the hit rate and novelty. In the present account, six case studies are described and the efficiency of mixing is evaluated. While sequentially combined 2D/3D similarity approach increases the hit rate significantly, sequential combination of 2D similarity with pharmacophore model or 3D docking enriched the resulting focused library with novel chemotypes. Parallel integrated approaches allowed the comparison of the various 2D and 3D methods and revealed that 2D similarity-based and 3D ligand and structure-based techniques are often complementary, and their combinations represent a powerful synergy. Finally, the lessons we learnt including the advantages and pitfalls of the described approaches are discussed.

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“…This relatively vast, diverse and unique chemical space was complemented with a focused set of 1,500 compounds synthesized at the University of Bari. To adjust the number of compounds to our screening capacity, an optimal diversity selection was performed [55]. The final screening collection was limited to a diverse selection of 30,000 compounds, a number that was fitting optimally our capacity for cytotoxicity screening.…”

Section: Methodsmentioning

confidence: 99%

A Chemocentric Approach to the Identification of Cancer Targets

Flachner¹,

Lőrincz²,

Carotti

et al. 2012

PLoS ONE

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A novel chemocentric approach to identifying cancer-relevant targets is introduced. Starting with a large chemical collection, the strategy uses the list of small molecule hits arising from a differential cytotoxicity screening on tumor HCT116 and normal MRC-5 cell lines to identify proteins associated with cancer emerging from a differential virtual target profiling of the most selective compounds detected in both cell lines. It is shown that this smart combination of differential in vitro and in silico screenings (DIVISS) is capable of detecting a list of proteins that are already well accepted cancer drug targets, while complementing it with additional proteins that, targeted selectively or in combination with others, could lead to synergistic benefits for cancer therapeutics. The complete list of 115 proteins identified as being hit uniquely by compounds showing selective antiproliferative effects for tumor cell lines is provided.

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Explicit Diversity Index (EDI): A Novel Measure for Assessing the Diversity of Compound Databases

Cited by 6 publications

References 42 publications

A Novel Small Molecule GDNF Receptor RET Agonist, BT13, Promotes Neurite Growth from Sensory Neurons in Vitro and Attenuates Experimental Neuropathy in the Rat

A Novel Small Molecule GDNF Receptor RET Agonist, BT13, Promotes Neurite Growth from Sensory Neurons in Vitro and Attenuates Experimental Neuropathy in the Rat

Rapid Identification of Potential Drug Candidates from Multi-Million Compounds’ Repositories. Combination of 2D Similarity Search with 3D Ligand/Structure Based Methods and In Vitro Screening

A Chemocentric Approach to the Identification of Cancer Targets

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