Design of a multi-purpose fragment screening library using molecular complexity and orthogonal diversity metrics

Lau, Wan F.; Withka, Jane M.; Hepworth, David; Magee, Thomas V.; Du, Yuhua J.; Bakken, Gregory A.; Miller, Michael D.; Hendsch, Zachary S.; Thanabal, V.; Kolodziej, Stephen A.; Li, Xing; Hu, Qiyue; Narasimhan, Lakshmi; Love, Robert A.; Charlton, Maura E.; Hughes, Samantha Jane; Hoorn, Willem P. van; Mills, James E.

doi:10.1007/s10822-011-9434-0

Cited by 60 publications

(32 citation statements)

References 51 publications

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“…10,11 Several of these have been optimized for diversity 10 and can recapitulate the chemotypes present in drug-like actives for several targets, 12,13 leading to active molecules in multiple screens. 14−17 Still, this is not the same as saying that fragment libraries cover most of biorelevant chemical space.…”

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confidence: 99%

Increasing Chemical Space Coverage by Combining Empirical and Computational Fragment Screens

et al. 2014

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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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confidence: 99%

Increasing Chemical Space Coverage by Combining Empirical and Computational Fragment Screens

et al. 2014

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“…Effective hit triage involved quick SAR mining; however, the number of small, common structural motifs lacking from commercial vendors was surprising. Clearly, carefully designed fragment libraries coupled with continuously filling the corporate collection with unique, follow-up compounds would fast-forward any fragment effort [27]. Additional orthogonal assay testing, e.g.…”

Section: Discussionmentioning

confidence: 99%

Novel isoquinolone PDK1 inhibitors discovered through fragment-based lead discovery

Johnson

Lingardo

et al. 2011

J Comput Aided Mol Des

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Phosphoinositide-dependent kinase-1 (PDK1) is a critical enzyme in the PI3K/AKT pathway and to the activation of AGC family protein kinases, including S6K, SGK, and PKC. Dysregulation of this pathway plays a key role in cancer cell growth, survival and tumor angiogenesis. As such, inhibitors of PDK1 offer the promise of a new therapeutic modality for cancer treatment. Fragment based drug screening has recently become a viable entry point for hit identification. In this work, NMR spectroscopy fragment screening of PDK1 afforded novel chemotypes as orthogonal starting points from HTS screening hits. Compounds identified as hits by NMR spectroscopy were tested in a biochemical assay, and fragments with activity in both assays were clustered. The Pfizer compound file was mined via substructure and 2D similarity search, and the chemotypes were prioritized by ligand efficiency (LE), SAR mining, chemical attractiveness, and chemical enablement of promising vectors. From this effort, an isoquinolone fragment hit, 5 (IC(50) 870 μM, LE = 0.39), was identified as a novel, ligand efficient inhibitor of PDK1 and a suitable scaffold for further optimization. Initially in the absence of crystallographic data, a fragment growing approach efficiently explored four vectors of the isoquinolone scaffold via parallel synthesis to afford a compound with crystallographic data, 16 (IC(50) 41.4 μM, LE = 0.33). Subsequent lead optimization efforts provided 24 (IC(50) 1.8 μM, LE = 0.42), with greater than fivefold selectivity against other key pathway kinases.

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“…Two recent publications describe approaches to fragment library construction-one from Pfizer describing a general purpose fragment library (Lau et al, 2011) and one from GlaxoSmithKline describing a kinasefocussed fragment library (Bamborough, Brown, Christopher, Chung, & Mellor, 2011). Another publication from Abbott (Akritopoulou-Zanze & Hajduk, 2009) describes the custom synthesis of more than 50 novel hinge-binding fragments to augment their library.…”

Section: Library Constructionmentioning

confidence: 99%

Fragment-Based Approaches to the Discovery of Kinase Inhibitors

Mortenson¹,

Berdini²,

O’Reilly³

2014

Methods in Enzymology

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Design of a multi-purpose fragment screening library using molecular complexity and orthogonal diversity metrics

Cited by 60 publications

References 51 publications

Increasing Chemical Space Coverage by Combining Empirical and Computational Fragment Screens

Increasing Chemical Space Coverage by Combining Empirical and Computational Fragment Screens

Novel isoquinolone PDK1 inhibitors discovered through fragment-based lead discovery

Fragment-Based Approaches to the Discovery of Kinase Inhibitors

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