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Article

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

TargetEx Ltd., Madách I. u. 31/2, 2120 Dunakeszi, Hungary
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Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Martin Vogt
Molecules 2021, 26(18), 5593; https://doi.org/10.3390/molecules26185593
Received: 10 August 2021 / Revised: 10 September 2021 / Accepted: 11 September 2021 / Published: 15 September 2021
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. View Full-Text
Keywords: 2D similarity search; virtual screening; pharmacophore matching; 3D modelling; in vitro screening 2D similarity search; virtual screening; pharmacophore matching; 3D modelling; in vitro screening
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MDPI and ACS Style

Szilágyi, K.; Flachner, B.; Hajdú, I.; Szaszkó, M.; Dobi, K.; Lőrincz, Z.; Cseh, S.; Dormán, G. 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. Molecules 2021, 26, 5593. https://doi.org/10.3390/molecules26185593

AMA Style

Szilágyi K, Flachner B, Hajdú I, Szaszkó M, Dobi K, Lőrincz Z, Cseh S, Dormán G. 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. Molecules. 2021; 26(18):5593. https://doi.org/10.3390/molecules26185593

Chicago/Turabian Style

Szilágyi, Katalin, Beáta Flachner, István Hajdú, Mária Szaszkó, Krisztina Dobi, Zsolt Lőrincz, Sándor Cseh, and György Dormán. 2021. "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" Molecules 26, no. 18: 5593. https://doi.org/10.3390/molecules26185593

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