Immunosuppressive Small Molecule Discovered by Structure‐Based Virtual Screening for Inhibitors of Protein–Protein Interactions

Geppert, Tim; Bauer, Stefanie; Hiss, Jan A.; Conrad, Elea; Reutlinger, Michael; Schneider, Petra; Weisel, Martin; Pfeiffer, Bernhard; Altmann, Karl‐Heinz; Waibler, Zoe

doi:10.1002/anie.201105901

Cited by 38 publications

(23 citation statements)

References 37 publications

(36 reference statements)

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“…[1] While targeting these interactions with large alpha-helical mimics [2–5] has been relatively successful, developing drug-like small molecule inhibitors of PPIs remains highly challenging. Recently, some success has resulted from the use of virtual screening [6] , fragment based approaches [7] and the targeting of hot-spots, [8] however the hit rates for protein interfaces remain low. [1c] …”

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confidence: 99%

Small‐Molecule Inhibitors of the Interaction between the E3 Ligase VHL and HIF1α

et al. 2012

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confidence: 99%

Small‐Molecule Inhibitors of the Interaction between the E3 Ligase VHL and HIF1α

et al. 2012

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“…Recent examples of PPI inhibitors identified by virtual screening are summarized in Table 4 and Fig. 141 More recently, Li's group reported a new computational strategy for PPI drug design by combining multiple ligand simultaneous docking (MLSD) and drug repositioning. On the basis of the reported examples, virtual screening is more successful for PPI targets with welldefined hot spots.…”

Section: Virtual Screeningmentioning

confidence: 99%

State-of-the-art strategies for targeting protein–protein interactions by small-molecule inhibitors

et al. 2015

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Targeting protein-protein interactions (PPIs) has emerged as a viable approach in modern drug discovery. However, the identification of small molecules enabling us to effectively interrupt their interactions presents significant challenges. In the recent past, significant advances have been made in the development of new biological and chemical strategies to facilitate the discovery process of small-molecule PPI inhibitors. This review aims to highlight the state-of-the-art technologies and the achievements made recently in this field. The "hot spots" of PPIs have been proved to be critical for small molecules to bind. Three strategies including screening, designing, and synthetic approaches have been explored for discovering PPI inhibitors by targeting the "hot spots". Although the classic high throughput screening approach can be used, fragment screening, fragment-based drug design and newly improved virtual screening are demonstrated to be more effective in the discovery of PPI inhibitors. In addition to screening approaches, design strategies including anchor-based and small molecule mimetics of secondary structures involved in PPIs have become powerful tools as well. Finally, constructing new chemically spaced libraries with high diversity and complexity is becoming an important area of interest for PPI inhibitors. The successful cases from the recent five year studies are used to illustrate how these approaches are implemented to uncover and optimize small molecule PPI inhibitors and notably some of them have become promising therapeutics.

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“…VS approaches have played a significant role in changing the notion about the undruggability of PPIs. Some of these VS studies took advantage of the hierarchical approach to identify initial hits that were later optimized into highly potent SMPPIIs [147,165,167,168,[175][176][177][178]. Some of these VS studies took advantage of the hierarchical approach to identify initial hits that were later optimized into highly potent SMPPIIs [147,165,167,168,[175][176][177][178].…”

Section: Hlvs For the Identification Of Smppiismentioning

confidence: 99%

Hierarchical virtual screening approaches in small molecule drug discovery

Kumar¹,

Zhang²

2015

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135

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Virtual screening has played a significant role in the discovery of small molecule inhibitors of therapeutic targets in last two decades. Various ligand and structure-based virtual screening approaches are employed to identify small molecule ligands for proteins of interest. These approaches are often combined in either hierarchical or parallel manner to take advantage of the strength and avoid the limitations associated with individual methods. Hierarchical combination of ligand and structure-based virtual screening approaches has received noteworthy success in numerous drug discovery campaigns. In hierarchical virtual screening, several filters using ligand and structure-based approaches are sequentially applied to reduce a large screening library to a number small enough for experimental testing. In this review, we focus on different hierarchical virtual screening strategies and their application in the discovery of small molecule modulators of important drug targets. Several virtual screening studies are discussed to demonstrate the successful application of hierarchical virtual screening in small molecule drug discovery.

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Immunosuppressive Small Molecule Discovered by Structure‐Based Virtual Screening for Inhibitors of Protein–Protein Interactions

Cited by 38 publications

References 37 publications

Small‐Molecule Inhibitors of the Interaction between the E3 Ligase VHL and HIF1α

Small‐Molecule Inhibitors of the Interaction between the E3 Ligase VHL and HIF1α

State-of-the-art strategies for targeting protein–protein interactions by small-molecule inhibitors

Hierarchical virtual screening approaches in small molecule drug discovery

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