Target‐Based Virtual Screening to Address Protein–Protein Interfaces

Spérandio, Olivier; Villoutreix, Bruno O.

doi:10.1002/9783527633326.ch16

Cited by 3 publications

(6 citation statements)

References 143 publications

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“…6 However, the most prevalent method, HTS, gives disappointing hit-rates relative to the cost and time expenditures involved, even if it is augmented by computational simulations based on matching virtual libraries with structural and physiochemical descriptors. 7,8 …”

Section: Introductionmentioning

confidence: 99%

“…6 However, the most prevalent method, HTS, gives disappointing hit rates relative to the cost and time expenditures involved, even if it is augmented by computational simulations based on matching virtual libraries with structural and physiochemical descriptors. 7,8 Compound libraries for HTS assembled to find small molecules that bind enzyme active sites, ion channels, and G protein-coupled receptors, and filtered for predicted oral bioavailabilities, 9,10 may not be suitable for PPI targets; it has been suggested this is one reason for the poor hit rates. 11 Despite this, there is no widely accepted notion of preferred small molecule chemotypes for these targets, except for small molecule mimics of ideal interface secondary structures.…”

Section: ■ Introductionmentioning

confidence: 99%

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Exploring Key Orientations at Protein–Protein Interfaces with Small Molecule Probes

Raghuraman²,

Pérez³

et al. 2012

J. Am. Chem. Soc.

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Small molecule probes that selectively perturb protein-protein interactions (PPIs) are pivotal to biomedical science, but their discovery is challenging. We hypothesized conformational resemblance of semi-rigid scaffolds expressing amino acid side-chains to PPI-interface regions could guide this process. Consequently, a data mining algorithm was developed to sample huge numbers of PPIs to find ones that match preferred conformers of a selected semi-rigid scaffold. Conformations of one such chemotype (1aaa; all methyl side-chains) matched several biomedically significant PPIs, including the dimerization interface of HIV-1 protease. Based on these observations, four molecules 1 with side-chains corresponding to the matching HIV-1 dimerization interface regions were prepared; all four inhibited HIV-1 protease via perturbation of dimerization. These data indicate this approach may inspire design of small molecule interface probes to perturb PPIs.

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Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Exploring Key Orientations at Protein–Protein Interfaces with Small Molecule Probes

Raghuraman²,

Pérez³

et al. 2012

J. Am. Chem. Soc.

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“…The six C α– C β coordinates of the preferred conformations were also overlaid on a huge database (>250k) of side‐chains on crystallographically characterized PPI interfaces (Exploring Key Orientations, EKO, see reference for details). Chemotype 1 has preferred conformations that overlay more often on secondary structures (rather than on regions that have no discernible secondary structures) than most of the minimalist mimics analyzed in a previous study.…”

Section: Figurementioning

confidence: 99%

Unconventional Secondary Structure Mimics: Ladder‐Rungs

et al. 2020

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Secondary structures tend to be recognizable because they have repeating structural motifs, but mimicry of these does not have to follow such well-defined patterns. Bioinformatics studies to match side-chain orientations of a novel hydantoin triazole chemotype (1) to protein-protein interfaces revealed it tends to align well across parallel and antiparallel sheets, like rungs on a ladder. One set of these overlays was observed for the protein-protein interaction uPA·uPAR. Consequently, chemotype 1 was made with appropriate side-chains to mimic uPA at this interface. Biophysical assays indicate these compounds did in fact bind uPAR, and elicit cellular responses that affected invasion, migration, and wound healing.

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“…High throughput screening, for instance, has been used oen for discovery of small molecules, but tends to give disappointing hit-rates relative to the cost and time expenditures involved. [35][36][37][38] The following argument can be made that resistance to MLN4924 is more likely than it would be for a small molecule that perturbs the NEDD8$NAE protein-protein interaction (PPI). Only non-extensive mutations are required to block pharmaceuticals binding nucleotide triphosphate binding sites.…”

Section: Introductionmentioning

confidence: 99%

“…High throughput screening, for instance, has been used often for discovery of small molecules, but tends to give disappointing hit-rates relative to the cost and time expenditures involved. 35–38…”

Section: Introductionmentioning

confidence: 99%