Challenges of fragment screening

Joseph‐McCarthy, Diane

doi:10.1007/s10822-009-9293-0

Cited by 14 publications

(9 citation statements)

References 25 publications

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“…Although based on the training set results we were not expecting better predictions, for the sake of completeness the remaining six protocols (4)(5)(6)(7)(8)(9) were also evaluated in the virtual screening of the SAMPL3-VS dataset.…”

Section: Fragment Virtual Screeningmentioning

confidence: 99%

“…The use of fragment-based approaches in drug design and particularly in virtual screening has known an explosive development in recent years [1][2][3][4][5][6][7]. In some instances, this approach has been successfully used as a less expensive alternative to the NMR and X-ray crystallography techniques for the assessment of binding site druggability [8].…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of docking performance in a blinded virtual screening of fragment-like trypsin inhibitors

Surpateanu

Iorga

2011

J Comput Aided Mol Des

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In this study, we have "blindly" assessed the ability of several combinations of docking software and scoring functions to predict the binding of a fragment-like library of bovine trypsine inhibitors. The most suitable protocols (involving Gold software and GoldScore scoring function, with or without rescoring) were selected for this purpose using a training set of compounds with known biological activities. The selected virtual screening protocols provided good results with the SAMPL3-VS dataset, showing enrichment factors of about 10 for Top 20 compounds. This methodology should be useful in difficult cases of docking, with a special emphasis on the fragment-based virtual screening campaigns.

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Section: Fragment Virtual Screeningmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Evaluation of docking performance in a blinded virtual screening of fragment-like trypsin inhibitors

Surpateanu

Iorga

2011

J Comput Aided Mol Des

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“…Virtual fragment screening also has proven useful and even for difficult test cases it can yield results that are significantly better than random screening. A number of challenges still remain, though. − Weak fragment hits are still often overlooked in favor of more potent HTS hits with poorer physical properties and ligand efficiencies. This bias is largely due to the fact that there is increasing pressure to shorten drug discovery timelines.…”

Section: Fblg Strategiesmentioning

confidence: 99%

Fragment-Based Lead Discovery and Design

Joseph‐McCarthy

Campbell

Kern

et al. 2014

J. Chem. Inf. Model.

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126

109

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Fragment-based lead discovery and design has and continues to show increasing promise in drug discovery. In this article, the current state of the art in terms of hot-spot characterization, fragment screening techniques, and fragment-based design is discussed. Three overall fragment-based lead generation strategies are explored and involve the chemical biology characterization of biological targets via fragment screening, fragment screening as a complementary approach to high-throughput screening of drug-like compounds, and direct fragment-based drug discovery, respectively. The evolution and development of fragment libraries is described. With an emphasis on computational approaches and the strategies applied at AstraZeneca, the review illustrates how integration of data from one regime can inform the design of experiments in the other, ultimately leading to the discovery of high quality chemical matter.

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“…Small chemical structures or fragments (usually of 150−250 molecular weight and weak affinity) are screened to probe the protein’s binding site to identify larger and more potent binding molecules. Although most platforms are laboratory-based, in silico techniques are emerging . Most computational methods employ well-established virtual screening techniques such as docking or pharmacophore generation together with a library of low molecular weight “fragments” to identify ligands that have a high probability of binding .…”

Section: Introductionmentioning

confidence: 99%

“…Although most platforms are laboratory-based, in silico techniques are emerging. 5 Most computational methods employ well-established virtual screening techniques such as docking or pharmacophore generation together with a library of low molecular weight "fragments" to identify ligands that have a high probability of binding. 6 Free-energy calculation by systematic sampling followed by de novo assembly of fragments has also been developed.…”

Section: Introductionmentioning

confidence: 99%

Chemical Fragments that Hydrogen Bond to Asp, Glu, Arg, and His Side Chains in Protein Binding Sites

2010

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We present an analysis of the chemical fragments from lead-like ligands in the Protein Data Bank (PDB) that form hydrogen bonds to the side chains of Asp, Glu, Arg, and His, which are the most common residues found in ligand binding sites. A fragment is defined as the largest ring assembly containing the atoms involved in hydrogen bonding. In total, 462 fragments were found in 2038 ligands from over 8000 protein-ligand structures in the PDB. The results show which fragments have a higher propensity for interaction with specific side chains. Some fragments interact with Asp but not with Glu, and vice versa, despite these side chains sharing the same chemical moiety. Arg side chains form hydrogen bonds almost exclusively with O-mediated ligands, and the fragments are the most diverse. Hydrogen bond distances from the imidazole of His showed a wider range than the other three amino acids.

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Challenges of fragment screening

Cited by 14 publications

References 25 publications

Evaluation of docking performance in a blinded virtual screening of fragment-like trypsin inhibitors

Evaluation of docking performance in a blinded virtual screening of fragment-like trypsin inhibitors

Fragment-Based Lead Discovery and Design

Chemical Fragments that Hydrogen Bond to Asp, Glu, Arg, and His Side Chains in Protein Binding Sites

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