Small and colorful stones make beautiful mosaics: fragment-based chemogenomics

Graaf, Chris de; Vischer, Henry F.; Kloe, Gerdien E. de; Kooistra, Albert J.; Nijmeijer, Saskia; Kuijer, Martien; Verheij, Mark H.P.; England, Paul; Muijlwijk‐Koezen, Jacqueline E. van; Leurs, Rob; Esch, Iwan J. P. de

doi:10.1016/j.drudis.2012.12.003

Cited by 29 publications

(71 citation statements)

References 60 publications

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“…Screening at 1 mM concentration resulted in 9% hit rate, followed by rapid hit expansion on druglike derivatives of fragment hits. Fragment screening of several histamine receptors subtypes and adrenergic β 2 receptor using radioligand has been reported (55,56). The somewhat low test concentration in the binding assays (10 µM) was justified by the 0.4-6% hit rate on the particular library.…”

Section: Binding Assaysmentioning

confidence: 99%

Fragment-based lead discovery on G-protein-coupled receptors

Visegrády

Keserü

2013

Expert Opinion on Drug Discovery

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KEYWORDS GPCR, fragment screening, virtual screening ARTICLE HIGHLIGHTS Recent advances in structural and biophysical characterization of GPCRs lead to improved efficacy of in vitro and in silico fragment-based lead discovery for GPCRs  Virtual fragment screening is a feasible approach for GPCR lead discovery  Multiple receptor conformations (including both experimental and theoretical models) might enhance the success rate of virtual fragment screening  Relevance of biophysical methods for fragment screening and evaluation on GPCRs has increased significantly  In vitro biological assays are suitable for functional screening on GPCRs 2 ABSTRACT Introduction G-protein-coupled receptors form one of the largest groups of potential targets for novel medications. Low druggability of many GPCR targets and inefficient sampling of chemical space in high throughput screening expertise however often hinder discovery of drug discovery leads for GPCRs. Fragment-based drug discovery is an alternative approach to the conventional strategy and has proven its efficiency on several enzyme targets. Based on developments in biophysical screening techniques, receptor stabilization and in vitro assays, virtual and experimental fragment screening and fragment-based lead discovery recently became applicable for GPCR targets.Areas covered Biophysical as well as biological detection techniques suitable to study GPCRs are reviewed, together with their applications to screen fragment libraries and identify fragment-size ligands of cell surface receptors. Several recent examples are presented, including both virtual and experimental protocols for fragment hit discovery and early hit to lead progress. Expert opinionWith the recent progress in biophysical detection techniques the advantages of fragmentbased drug discovery could be exploited for GPCR targets. Structural information on GPCRs will be more abundantly available for early stages of drug discovery projects, providing information on the binding process and efficiently supporting the progression of fragment hit to lead. In silico approaches in combination with biological assays can be used to address structurally challenging GPCRs and confirm biological relevance of interaction early in the drug discovery project.3

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Section: Binding Assaysmentioning

confidence: 99%

Fragment-based lead discovery on G-protein-coupled receptors

Visegrády

Keserü

2013

Expert Opinion on Drug Discovery

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“…Within the context of FBDD, fragment-based screening is a more efficient way to sample chemical space and generally yields higher hit rates than classical high-throughput screening (HTS) campaigns of larger, drug-like compound. 11,14,15 Biochemical and biophysical fragment screening studies of small chemical libraries (circa 25-1010 compounds) against different GPCRs have been reported with 0.4-14% hit rates yielding several new chemical starting points for fragment-based GPCR ligand optimization. 14,[16][17][18][19][20][21][22] So far only few experimental screens of the same fragment library against multiple GPCR targets have been reported 14,16 that can provide information about the molecular determinants of GPCR-ligand selectivity by fragment-based chemogenomics analyses.…”

Section: Introductionmentioning

confidence: 99%

“…11,14,15 Biochemical and biophysical fragment screening studies of small chemical libraries (circa 25-1010 compounds) against different GPCRs have been reported with 0.4-14% hit rates yielding several new chemical starting points for fragment-based GPCR ligand optimization. 14,[16][17][18][19][20][21][22] So far only few experimental screens of the same fragment library against multiple GPCR targets have been reported 14,16 that can provide information about the molecular determinants of GPCR-ligand selectivity by fragment-based chemogenomics analyses. 14,23 Virtual fragment screening approaches, the in silico prediction of fragment binding to protein binding sites that has the potential to explore protein-ligand space more extensively, have been successfully applied to identify new fragment-like ligands for several GPCR targets, with 20-73% hit rates (% of experimentally tested in silico hits with detectable binding affinity).…”

Section: Introductionmentioning

confidence: 99%

“…14,[16][17][18][19][20][21][22] So far only few experimental screens of the same fragment library against multiple GPCR targets have been reported 14,16 that can provide information about the molecular determinants of GPCR-ligand selectivity by fragment-based chemogenomics analyses. 14,23 Virtual fragment screening approaches, the in silico prediction of fragment binding to protein binding sites that has the potential to explore protein-ligand space more extensively, have been successfully applied to identify new fragment-like ligands for several GPCR targets, with 20-73% hit rates (% of experimentally tested in silico hits with detectable binding affinity). 18,20,22,[24][25][26][27] While ligand-based virtual screening methods often only allow the identification of chemically similar ligands, protein-based virtual screening approaches potentially offer the possibility of scaffold hopping, the discovery of ligands with new chemical functional groups.…”

Section: Introductionmentioning

confidence: 99%

“…1) have resulted from high-throughput screening (HTS) campaigns and subsequent medicinal chemistry programs. [4][5][6][7][8] Fragment-based drug discovery (FBDD) 9-11 is a new paradigm in drug discovery that utilizes small molecules (molecular weight ≤300 Dalton, heavy atoms ≤22) [12][13][14] as starting points for hit optimization. Within the context of FBDD, fragment-based screening is a more efficient way to sample chemical space and generally yields higher hit rates than classical high-throughput screening (HTS) campaigns of larger, drug-like compound.…”

Section: Introductionmentioning

confidence: 99%

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Structure-based virtual screening for fragment-like ligands of the G protein-coupled histamine H₄receptor

et al. 2015

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We have explored the possibilities and challenges of structure-based virtual screening (SBVS) against the human histamine H 4 receptor (H 4 R), a key player in inflammatory responses. Several SBVS strategies, employing different H 4 R ligand conformations, were validated and optimized with respect to their ability to discriminate small fragment-like H 4 R ligands from true inactive fragments, and compared to ligand-based virtual screening (LBVS) approaches. SBVS studies with a molecular interaction fingerprint (IFP) scoring method enabled the identification of H 4 R ligands that were not identified in LBVS runs, demonstrating the scaffold hopping potential of combining molecular docking and IFP scoring. Retrospective VS evaluations against H 4 R homology models based on the histamine H 1 receptor (H 1 R) crystal structure did not give higher enrichments of H 4 R ligands than H 4 R models based on the beta-2 adrenergic receptor (β 2 R). Complementary prospective SBVS studies against β 2 R-based and H 1 R-based H 4 R homology models led to the discovery of different new fragment-like H 4 R ligand chemotypes. Of the 37 tested compounds, 9 fragments (representing 5 different scaffolds) had affinities between 0.14 and 6.3 μM at the H 4 R.

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