ArticleACS chemical biology2014
Increasing chemical space coverage by combining empirical and computational fragment screens.
Article in ACS chemical biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed.
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- Machine Learning and Deep Learning Models for Predicting Noncovalent Inhibitors of AmpC β-Lactamase.ACS omega · 2024Article
- Dye degradation and antimicrobial efficacy of cesium-doped YRSC advances · 2024Article
- Improved Detection of Drug-Induced Liver Injury by Integrating PredictedChemical research in toxicology · 2024Article
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- Improved Detection of Drug-Induced Liver Injury by Integrating PredictedbioRxiv : the preprint server for biology · 2024Article
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- Antimicrobial potential and rhodamine B dye degradation using graphitic carbon nitride and polyvinylpyrrolidone doped bismuth tungstate supported with in silico molecular docking studies.Scientific reports · 2023Article
- Catalytic performance and antibacterial behaviour with molecular docking analysis of silver and polyacrylic acid doped graphene quantum dots.RSC advances · 2023Article
- Catalytic evaluation andRSC advances · 2023Article
- Structure-Based Discovery of Inhibitors of the SARS-CoV-2 Nsp14 N7-Methyltransferase.Journal of medicinal chemistry · 2023Article
- La-Doped CeOACS omega · 2023Article
- Bactericidal Action and Industrial Dye Degradation of Graphene Oxide and Polyacrylic Acid-Doped SnOACS omega · 2023Article
- A semi-automated material exploration scheme to predict the solubilities of tetraphenylporphyrin derivatives.Communications chemistry · 2022Article
- Class C β-Lactamases: Molecular Characteristics.Clinical microbiology reviews · 2022Review
- Inverse Mixed-Solvent Molecular Dynamics for Visualization of the Residue Interaction Profile of Molecular Probes.International journal of molecular sciences · 2022Article
- Photocatalytic, Bactericidal and Molecular Docking Analysis of Annealed Tin Oxide Nanostructures.Nanoscale research letters · 2021Article
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Authors and funding
9 authors.
Funding
Abstract
Most libraries for fragment-based drug discovery are restricted to 1,000-10,000 compounds, but over 500,000 fragments are commercially available and potentially accessible by virtual screening. Whether this larger set would increase chemotype coverage, and whether a computational screen can pragmatically prioritize them, is debated. To investigate this question, a 1281-fragment library was screened by nuclear magnetic resonance (NMR) against AmpC β-lactamase, and hits were confirmed by surface plasmon resonance (SPR). Nine hits with novel chemotypes were confirmed biochemically with KI values from 0.2 to low mM. We also computationally docked 290,000 purchasable fragments with chemotypes unrepresented in the empirical library, finding 10 that had KI values from 0.03 to low mM. Though less novel than those discovered by NMR, the docking-derived fragments filled chemotype holes from the empirical library. Crystal structures of nine of the fragments in complex with AmpC β-lactamase revealed new binding sites and explained the relatively high affinity of the docking-derived fragments. The existence of chemotype holes is likely a general feature of fragment libraries, as calculation suggests that to represent the fragment substructures of even known biogenic molecules would demand a library of minimally over 32,000 fragments. Combining computational and empirical fragment screens enables the discovery of unexpected chemotypes, here by the NMR screen, while capturing chemotypes missing from the empirical library and tailored to the target, with little extra cost in resources.
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