Fragment-based identification of druggable ‘hot spots’ of proteins using Fourier domain correlation techniques

Brenke, Ryan; Kozakov, Dima; Chuang, Gwo-Yu; Beglov, Dmitri; Hall, David R.; Landon, Melissa R.; Mattos, Carla; Vajda, Sándor

doi:10.1093/bioinformatics/btp036

Cited by 393 publications

(604 citation statements)

References 30 publications

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“…In silico probing of the three-dimensional surface of eIF4E for potential drug binding sites by computational solvent mapping (15) revealed the presence of five shallow pockets that form an elongated binding site and could support small molecule interactions ( Fig. 2A).…”

Section: Modeling Binding Of 4e1rcat To Eif4e Predicts Interference Wmentioning

confidence: 99%

Reversing chemoresistance by small molecule inhibition of the translation initiation complex eIF4F

Cencic¹,

Hall

Robert³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The authors note that, due to a printer's error, on page 3787, right column, first paragraph, lines 8-20, "Although significant evidence supports a primary role for the 5-HT transporter in the reinforcing properties of psychostimulants (35-37), SERT blockade also appears to contribute to reinforcement (38-40).Indeed, SERT appears to be primarily responsible for the sustained reinforcing properties of cocaine in the 5-HT transporter-KO mouse (22,23,(39)(40)(41). The significant compensatory alterations evident in 5-HT transporter-KO mice encouraged Chen and colleagues (42, 43) to develop a mouse bearing knock-in mutations in 5-HT transporter that, in vitro, reduced cocaine potency. Studies with these mice have yielded convincing evidence that 5-HT transporter is a key determinant of many synaptic and behavioral actions of cocaine" should instead appear as "Although significant evidence supports a primary role for the DA transporter in the reinforcing properties of psychostimulants (35-37), SERT blockade also appears to contribute to reinforcement (38-40). Indeed, SERT appears to be primarily responsible for the sustained reinforcing properties of cocaine in the DA transporter-KO mouse (22,23,(39)(40)(41). The significant compensatory alterations evident in DA transporter-KO mice encouraged Chen and colleagues (42, 43) to develop a mouse bearing knock-in mutations in the DA transporter that, in vitro, reduced cocaine potency. Studies with these mice have yielded convincing evidence that the DA transporter is a key determinant of many synaptic and behavioral actions of cocaine." www.pnas.org/cgi

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Section: Modeling Binding Of 4e1rcat To Eif4e Predicts Interference Wmentioning

confidence: 99%

Reversing chemoresistance by small molecule inhibition of the translation initiation complex eIF4F

Cencic¹,

Hall

Robert³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

151

184

View full text Add to dashboard Cite

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“…2. Pocket 1 comprises the effector binding loop (residues [30][31][32][33][34][35][36][37][38][39][40], β2 (residues 55 and 57), and several residues in α-helix 1. Pocket 2 involves the core β-strands 1 and 2, part of the effector loop, and switch 2.…”

Section: Resultsmentioning

confidence: 99%

Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function

Hocker

Cho

Chen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

133

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Aberrant signaling by oncogenic mutant rat sarcoma (Ras) proteins occurs in ∼15% of all human tumors, yet direct inhibition of Ras by small molecules has remained elusive. Recently, several smallmolecule ligands have been discovered that directly bind Ras and inhibit its function by interfering with exchange factor binding. However, it is unclear whether, or how, these ligands could lead to drugs that act against constitutively active oncogenic mutant Ras. Using a dynamics-based pocket identification scheme, ensemble docking, and innovative cell-based assays, here we show that andrographolide (AGP)-a bicyclic diterpenoid lactone isolated from Andrographis paniculata-and its benzylidene derivatives bind to transient pockets on Kirsten-Ras (K-Ras) and inhibit GDP-GTP exchange. As expected for inhibitors of exchange factor binding, AGP derivatives reduced GTP loading of wild-type K-Ras in response to acute EGF stimulation with a concomitant reduction in MAPK activation. Remarkably, however, prolonged treatment with AGP derivatives also reduced GTP loading of, and signal transmission by, oncogenic mutant K-RasG12V. In sum, the combined analysis of our computational and cell biology results show that AGP derivatives directly bind Ras, block GDP-GTP exchange, and inhibit both wild-type and oncogenic K-Ras signaling. Importantly, our findings not only show that nucleotide exchange factors are required for oncogenic Ras signaling but also demonstrate that inhibiting nucleotide exchange is a valid approach to abrogating the function of oncogenic mutant Ras.cancer | molecular dynamics | allosteric site | drug design

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“…Since PPI often lack obvious cavities, docking must be preceded by a search for potentially dockable (bindable) cavities and grooves. Virtual screening has demonstrated particular promise for docking fragments, and researchers are actively working to integrate virtual screening and fragment discovery for PPI inhibitors (Betzi et al 2009;Fuller et al 2009;Reynes et al 2010;Vajda and Kozakov 2009;Brenke et al 2009). The convergence of PPI surface simulation, target-optimized docking procedures, and PPI inhibitororiented virtual compound collections presents an exciting opportunity to drug the hardest of PPI targets.…”

Section: Methodsmentioning

confidence: 99%

Small-Molecule Inhibitors of IL-2/IL-2R: Lessons Learned and Applied

Wilson

Arkin

2010

Current Topics in Microbiology and Immunology

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Fragment-based identification of druggable ‘hot spots’ of proteins using Fourier domain correlation techniques

Abstract: FTMAP is available as a server at http://ftmap.bu.edu/.

Cited by 393 publications

References 30 publications

Reversing chemoresistance by small molecule inhibition of the translation initiation complex eIF4F

Reversing chemoresistance by small molecule inhibition of the translation initiation complex eIF4F

Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function

Small-Molecule Inhibitors of IL-2/IL-2R: Lessons Learned and Applied

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