Fragment screening to predict druggability (ligandability) and lead discovery success

Edfeldt, Fredrik; Folmer, R.H.A.; Breeze, Alexander L.

doi:10.1016/j.drudis.2011.02.002

Cited by 188 publications

(190 citation statements)

References 12 publications

Supporting

Mentioning

183

Contrasting

Unclassified

Order By: Relevance

“…However, their extensive regulatory role in biological mechanisms dictates that high-quality tool compounds modulating PPIs are urgently required as probes of healthy/disease biology and to provide starting points for drug discovery. Here, PPIs present a further challenge in that the interacting surfaces are larger, flatter, and generally deficient in the "binding-pockets" that define conventional ligandable 15,16 proteins, 9 although identification of hotspots 17 permits a binding site to be defined. This challenge is sufficiently daunting that, until recently, PPIs were considered too challenging to modulate using small-molecules and amenable only to modulation using biologics.…”

Section: Intentionally Targetingmentioning

confidence: 99%

Modulators of Protein–Protein Interactions

et al. 2014

View full text Add to dashboard Cite

Direct interactions between proteins are essential for the regulation of their functions in biological pathways. Targeting the complex network of protein−protein interactions (PPIs) has now been widely recognized as an attractive means to therapeutically intervene in disease states. Even though this is a challenging endeavor and PPIs have long been regarded as "undruggable" targets, the last two decades have seen an increasing number of successful examples of PPI modulators, resulting in growing interest in this field. PPI modulation requires novel approaches and the integrated efforts of multiple disciplines to be a fruitful strategy. This perspective focuses on the hub-protein 14-3-3, which has several hundred identified protein interaction partners, and is therefore involved in a wide range of cellular processes and diseases. Here, we aim to provide an integrated overview of the approaches explored for the modulation of 14-3-3 PPIs and review the examples resulting from these efforts in both inhibiting and stabilizing specific 14-3-3 protein complexes by small molecules, peptide mimetics, and natural products.

show abstract

Section: Intentionally Targetingmentioning

confidence: 99%

Modulators of Protein–Protein Interactions

et al. 2014

View full text Add to dashboard Cite

show abstract

“…6 Ligand efficiency metrics are often used to judge whether increases in affinity are acceptable. 7 As mentioned above, an alternative use of fragments is to assess the chemical tractability of a target, 8 but the design and screening principles discussed here are broadly the same for such usage.…”

Section: Introductionmentioning

confidence: 99%

Design Principles for Fragment Libraries: Maximizing the Value of Learnings from Pharma Fragment-Based Drug Discovery (FBDD) Programs for Use in Academia

et al. 2016

View full text Add to dashboard Cite

Fragment-based drug discovery (FBDD) is well suited for discovering both drug leads and chemical probes of protein function: it can cover broad swaths of chemical space and allows the use of creative chemistry. FBDD is widely implemented for lead discovery in industry, but is sometimes used less systematically in academia. Design principles and implementation approaches for fragment libraries are continually evolving, and the lack of up-to-date guidance may prevent more effective application of FBDD in academia. This Perspective explores many of the theoretical, practical, and strategic considerations that occur within FBDD programs, including the optimal size, complexity, physicochemical profile, and shape profile of fragments in FBDD libraries, as well as compound storage, evaluation, and screening technologies. This compilation of industry experience in FBDD will hopefully be useful for those pursuing FBDD in academia.Rules are for the obedience of fools and the guidance of wise men.Harry Day, Royal Air Force (1898-1977

show abstract

“…Druggability evaluated the probability of unearthing small molecules which alters the function of the drug targets to which they bind in a way that benefits the patient therapeutically [36]. We identified 47 proteins with a significantly higher similarity to the binders of these drug targeted proteins.…”

Section: Prioritization Of Drug Targetsmentioning

confidence: 99%