scholarly journals Cation–π interactions in CREBBP bromodomain inhibition: an electrostatic model for small-molecule binding affinity and selectivity

2016 ◽  
Vol 14 (46) ◽  
pp. 10926-10938 ◽  
Author(s):  
Wilian A. Cortopassi ◽  
Kiran Kumar ◽  
Robert S. Paton
Keyword(s):  
Binding Affinity ◽  
Small Molecule ◽  
Interaction Strength ◽  
Electrostatic Model ◽  
New Model ◽  
Π Interactions

A new model is presented to explain and predict binding affinity of aromatic and heteroaromatic ligands for the CREBBP bromodomain based on cation–π interaction strength.

scholarly journals Effect of Small-Molecule–Binding Affinity on Tumor Uptake In Vivo: A Systematic Study Using a Pretargeted Bispecific Antibody

2012 ◽  
Vol 11 (6) ◽  
pp. 1365-1372 ◽  
Author(s):  
Kelly Davis Orcutt ◽  
John J. Rhoden ◽  
Benjamin Ruiz-Yi ◽  
John V. Frangioni ◽  
K. Dane Wittrup
Keyword(s):  
Binding Affinity ◽  
Small Molecule ◽  
Systematic Study ◽  
Bispecific Antibody ◽  
Tumor Uptake

DeepCDA: deep cross-domain compound–protein affinity prediction through LSTM and convolutional neural networks

2020 ◽  
Vol 36 (17) ◽  
pp. 4633-4642 ◽  
Author(s):  
Karim Abbasi ◽  
Parvin Razzaghi ◽  
Antti Poso ◽  
Massoud Amanlou ◽  
Jahan B Ghasemi ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Short Term Memory ◽  
Domain Adaptation ◽  
Interaction Strength ◽  
Training Data ◽  
Second Phase ◽  
Cross Domain ◽  
Third Phase ◽  
Reliable Model ◽  
Occurrence Patterns

Abstract Motivation An essential part of drug discovery is the accurate prediction of the binding affinity of new compound–protein pairs. Most of the standard computational methods assume that compounds or proteins of the test data are observed during the training phase. However, in real-world situations, the test and training data are sampled from different domains with different distributions. To cope with this challenge, we propose a deep learning-based approach that consists of three steps. In the first step, the training encoder network learns a novel representation of compounds and proteins. To this end, we combine convolutional layers and long-short-term memory layers so that the occurrence patterns of local substructures through a protein and a compound sequence are learned. Also, to encode the interaction strength of the protein and compound substructures, we propose a two-sided attention mechanism. In the second phase, to deal with the different distributions of the training and test domains, a feature encoder network is learned for the test domain by utilizing an adversarial domain adaptation approach. In the third phase, the learned test encoder network is applied to new compound–protein pairs to predict their binding affinity. Results To evaluate the proposed approach, we applied it to KIBA, Davis and BindingDB datasets. The results show that the proposed method learns a more reliable model for the test domain in more challenging situations. Availability and implementation https://github.com/LBBSoft/DeepCDA.

scholarly journals Wnt Binding Affinity Prediction for Putative Frizzled-Type Cysteine-Rich Domains

2019 ◽  
Vol 20 (17) ◽  
pp. 4168 ◽  
Author(s):  
Mark Agostino ◽  
Sebastian Öther-Gee Pohl
Keyword(s):  
Binding Energy ◽  
Prediction Model ◽  
Binding Affinity ◽  
Wnt Signalling ◽  
Binding Affinity Prediction ◽  
New Model ◽  
Affinity Prediction ◽  
Frizzled Receptors ◽  
Canonical Wnt ◽  
Related Proteins

Several proteins other than the frizzled receptors (Fzd) and the secreted Frizzled-related proteins (sFRP) contain Fzd-type cysteine-rich domains (CRD). We have termed these domains “putative Fzd-type CRDs”, as the relevance of Wnt signalling in the majority of these is unknown; the RORs, an exception to this, are well known for mediating non-canonical Wnt signalling. In this study, we have predicted the likely binding affinity of all Wnts for all putative Fzd-type CRDs. We applied both our previously determined Wnt‒Fzd CRD binding affinity prediction model, as well as a newly devised model wherein the lipid term was forced to contribute favourably to the predicted binding energy. The results obtained from our new model indicate that certain putative Fzd CRDs are much more likely to bind Wnts, in some cases exhibiting selectivity for specific Wnts. The results of this study inform the investigation of Wnt signalling modulation beyond Fzds and sFRPs.

The binding affinity of uncharged aromatic solutes for negatively charged resins is enhanced by cations via cation–π interactions: The case of sodium ion and arginine

2019 ◽  
Vol 1595 ◽  
pp. 97-107 ◽  
Author(s):  
Atsushi Hirano ◽  
Kazuki Iwashita ◽  
Tomoto Ura ◽  
Shun Sakuraba ◽  
Kentaro Shiraki ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Sodium Ion ◽  
Π Interactions

Evidence for CCl/CBr⋅⋅⋅π Interactions as an Important Contribution to Protein-Ligand Binding Affinity

2009 ◽  
Vol 121 (16) ◽  
pp. 2955-2960 ◽  
Author(s):  
Hans Matter ◽  
Marc Nazaré ◽  
Stefan Güssregen ◽  
David W. Will ◽  
Herman Schreuder ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Binding Affinity ◽  
Π Interactions

The Lipid Addiction of Diffuse Large B-Cell Lymphoma (DLBCL) and Potential Treatment Strategies with Novel Fatty Acid Synthase (FASN) Small Molecule Inhibitors

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4490-4490 ◽  
Author(s):  
Ravi Dashnamoorthy ◽  
Nassera Abermil ◽  
Afshin Behesti ◽  
Paige Kozlowski ◽  
Frederick Lansigan ◽  
...  
Keyword(s):  
Cell Death ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Cell Survival ◽  
Binding Affinity ◽  
Cell Lines ◽  
Small Molecule ◽  
Research Funding ◽  
Fatty Acid Synthase ◽  
The Impact

Abstract Background: Fatty acid (FA) metabolism is altered in several cancers through increased de novo synthesis of lipids via up-regulation fatty acid synthase (FASN) and increased utilization of lipids via β-oxidation. We investigated the dependence of DLBCL survival on FA metabolism. In addition, we examined novel FASN inhibitors TVB3567 and TVB3166 in comparison with cerulenin for the effects on cell survival and PI3K and MAPK-related biological pathways associated with tumor-related FA metabolism in DLBCL. Methods: FASN inhibitors, TVB3567 and TVB3166 (3V Biosciences, CA), cerulenin (FASN inhibitor), orlistat (anti-lipoprotein lipase (LPL) and FASN), PI3K/mTOR, and MEK small molecule inhibitors were studied in OCI-LY3, OCI-LY19, SUDHL4, SUDHL6, and SUDHL10 DLBCL cell lines for the effects of FA inhibition on lipid metabolism, cell signaling, and cell death. The effects of FASN inhibition on global gene expression profile (GEP) were also determined with Affymetrix Human 2.0 ST Genechip with Gene set enrichment analysis (GSEA). We also utilized short hairpin RNA interference (shRNA) to study interactions between FASN and PI3K/MAPK signaling. Finally, AutoDock Vina software (autodock.scripps.edu) was utilized to analyze drug target (FASN enzyme) binding affinity and assist in the design of FASN inhibitors with higher target binding affinity. Results: DLBCL cell lines OCI-LY3, SUDHL4, and SUDHL6 grown in the presence of lipoprotein-depleted serum showed exquisite sensitivity to lipid deprivation resulting in near complete cytotoxicity by MTT. Lipid deprivation-induced apoptotic cell death, detected as cleaved caspase 3 and PARP and Annexin-V/PI positivity, in these cells. Further, these effects were completely rescued by Very Low Density Lipoprotein (VLDL) supplementation to growth medium in SUDHL4 confirming the high lipid-dependency on cell survival in DLBCL. Treatment with pharmacological inhibitors of FASN (ie, TVB3567, TVB3166, cerulenin, or orlistat) resulted in a dose- and time-dependent reduction in cell viability in all DLBCL cell lines. Ingenuity Pathway Analysis (IPA) from GEP with cerulenin-treated OCI-LY3 showed prominent suppression of CD40, TNF, and NFκB dependent inflammatory responses as well as activation of apoptosis as predominant biological activities including significant down-regulation of genes involved in Krebs cycle and p38 MAPK pathways. Interestingly, upstream regulation by IPA predicted activation of MEK/ERK and MYC-dependent functions; and in OCI-LY3 with shRNA knock down of FASN, we observed constitutive activation of ERK as detected with increased phosphorylation by western blot. Activation of MEK/ERK and MYC is expected in part owing to metabolic stress induced by FASN inhibition. Considering the impact of MEK/ERK pathways on lipid metabolism, we next investigated the impact of MEK/ERK on FA metabolism. FASN was significantly decreased following MEK or ERK shRNA in OCILY-3 and SUDHL10 cells. Similarly, pharmacological inhibition of MEK or PI3K/mTOR (using novel small molecule agents AZD6244 (selumetinib) or BEZ235, respectively) resulted in marked down-regulation of FASN expression. Based on these results, FASN inhibition appears to a promising therapeutic target for the treatment of DLBCL, however attaining clinical efficacy with existing compounds require the effective drug concentration to be within the nanomolar range. Thus, we utilized AutoDock to determine drug docking enzyme inhibition constant (ki). We identified high ki values of 33μM and 180μM for Cerulenin and Orilstat, respectively. Therefore, we have developed/constructed modified novel and potent anti-FA compounds with ki <1μM that are currently being investigated. Conclusions: Collectively, we demonstrated that DLBCL cell survival is highly dependent on FA metabolism and that targeting lipid metabolism may be harnessed as a potential therapeutic strategy. We also showed that MEK/ERK-dependent mechanisms are intimately involved in promoting lipid addiction in DLBCL cells. Further investigation is warranted to delineate the mechanisms through which MEK/ERK regulate FASN expression and to determine in vivo implications of FASN inhibition on DLBCL tumor growth. In addition, continued development, design, and enhancement are needed to construct the most optimal anti-FA therapeutic agents. Disclosures Lansigan: Teva Pharmaceuticals: Research Funding; Spectrum Pharmaceuticals: Research Funding.

The influence of directed π–π interactions in solution on the thin film organic semiconductor device properties of small molecule polymer blends

Soft Matter ◽  
2011 ◽  
Vol 7 (15) ◽  
pp. 7065 ◽  
Author(s):  
Marie-Beatrice Madec ◽  
Sean Butterworth ◽  
Pablo Taboada ◽  
Richard Heenan ◽  
Mark Geoghegan ◽  
...  
Keyword(s):  
Thin Film ◽  
Polymer Blends ◽  
Small Molecule ◽  
Organic Semiconductor ◽  
Semiconductor Device ◽  
Π Interactions ◽  
Device Properties

scholarly journals Identification of small molecule compounds with higher binding affinity to guanine deaminase (cypin) than guanine

2010 ◽  
Vol 18 (18) ◽  
pp. 6748-6755 ◽  
Author(s):  
José R. Fernández ◽  
Eric S. Sweet ◽  
William J. Welsh ◽  
Bonnie L. Firestein
Keyword(s):  
Binding Affinity ◽  
Small Molecule ◽  
Guanine Deaminase

Binding Affinity of a Small Molecule to an Amorphous Polymer in a Solvent. Part 2: Preferential Binding to Local Sites on a Surface

Langmuir ◽  
2011 ◽  
Vol 27 (20) ◽  
pp. 12396-12404 ◽  
Author(s):  
Surasak Chunsrivirot ◽  
Erik Santiso ◽  
Bernhardt L. Trout
Keyword(s):  
Binding Affinity ◽  
Small Molecule ◽  
Amorphous Polymer ◽  
Preferential Binding
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