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

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

scholarly journals Quantitative Structure-Activity Relationship of Various Endogenous Estrogen Metabolites for Human Estrogen Receptor α and β Subtypes: Insights into the Structural Determinants Favoring a Differential Subtype Binding

Endocrinology ◽  
2006 ◽  
Vol 147 (9) ◽  
pp. 4132-4150 ◽  
Author(s):  
Bao Ting Zhu ◽  
Gui-Zhen Han ◽  
Joong-Youn Shim ◽  
Yujing Wen ◽  
Xiang-Rong Jiang
Keyword(s):  
Estrogen Receptor ◽  
Binding Affinity ◽  
Quantitative Structure Activity Relationship ◽  
Activity Relationship ◽  
Quantitative Structure ◽  
Structural Determinants ◽  
Structure Activity ◽  
Preferential Binding ◽  
Human Estrogen Receptor ◽  
Endogenous Estrogen

To search for endogenous estrogens that may have preferential binding affinity for human estrogen receptor (ER) α or β subtype and also to gain insights into the structural determinants favoring differential subtype binding, we studied the binding affinities of 74 natural or synthetic estrogens, including more than 50 steroidal analogs of estradiol-17β (E2) and estrone (E1) for human ERα and ERβ. Many of the endogenous estrogen metabolites retained varying degrees of similar binding affinity for ERα and ERβ, but some of them retained differential binding affinity for the two subtypes. For instance, several of the D-ring metabolites, such as 16α-hydroxyestradiol (estriol), 16β-hydroxyestradiol-17α, and 16-ketoestrone, had distinct preferential binding affinity for human ERβ over ERα (difference up to 18-fold). Notably, although E2 has nearly the highest and equal binding affinity for ERα and ERβ, E1 and 2-hydroxyestrone (two quantitatively predominant endogenous estrogens in nonpregnant woman) have preferential binding affinity for ERα over ERβ, whereas 16α-hydroxyestradiol (estriol) and other D-ring metabolites (quantitatively predominant endogenous estrogens formed during pregnancy) have preferential binding affinity for ERβ over ERα. Hence, facile metabolic conversion of parent hormone E2 to various metabolites under different physiological conditions may serve unique functions by providing differential activation of the ERα or ERβ signaling system. Lastly, our computational three-dimensional quantitative structure-activity relationship/comparative molecular field analysis of 47 steroidal estrogen analogs for human ERα and ERβ yielded useful information on the structural features that determine the preferential activation of the ERα and ERβ subtypes, which may aid in the rational design of selective ligands for each human ER subtype.

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.

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

Molecular dynamics simulation elucidates the preferential binding affinity of sodium and tetramethylammonium ions for tetrameric Nafion unit under aqueous conditions

RSC Advances ◽  
2016 ◽  
Vol 6 (100) ◽  
pp. 97961-97968 ◽  
Author(s):  
Soumadwip Ghosh ◽  
Rajarshi Chakrabarti
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Binding Affinity ◽  
Dynamics Simulation ◽  
Binding Interaction ◽  
Preferential Binding ◽  
Aqueous Conditions

Preferential binding interaction of sodium and tetramethylammonium cations with Nafion pendant and backbone sites respectively.

scholarly journals Entropy of Stapled Peptide Inhibitors in Free State is the Major Contributor to the Improvement of Binding Affinity

2021 ◽  
Author(s):  
Ilona Christy Unarta ◽  
Jianchao Xu ◽  
Yuan Shang ◽  
Carina Hey Pui Cheung ◽  
Ruichi Zhu ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Small Molecule ◽  
Protein Interaction ◽  
Small Molecule Inhibitors ◽  
Peptide Inhibitors ◽  
Major Contributor ◽  
Protein Targets ◽  
Stapled Peptide ◽  
Protein Protein Interaction ◽  
Energetic Interactions

Stapled peptides are promising protein-protein interaction (PPI) inhibitors that can increase binding potency. Different from small-molecule inhibitors in which binding mainly depends on energetic interactions with their protein targets, stapled...

scholarly journals Targeting dysregulation signatures of p53-MDM2 interactions to identify newer small molecule inhibitors for cancer therapy: Insight from computational direction

2021 ◽  
Author(s):  
Prosper Obed Chukwuemeka ◽  
Haruna Isiyaku Umar ◽  
Opeyemi Iwaloye ◽  
Oluwaseyi Matthew Oretade ◽  
Christopher Busayo Olowosoke ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Therapeutic Option ◽  
Pharmacophore Model ◽  
In Vivo Studies ◽  
Hydrogen Bond Acceptor ◽  
Potential Inhibitors

Abstract Dysregulation of the p53-MDM2 interactions has been implicated in majority of human tumors presenting a target for finding small molecule inhibitors. In this study, a training set of 17 experimentally tested inhibitors of MDM2 was used to develop series of pharmacophore models among which a four-featured (AHRR_1) model with one hydrogen bond acceptor, one hydrophobic group and two aromatic ring features and characterized by a survival score of 4.176 was considered significant among the top ranked generated hypothesis. Further, the model was validated by an external set of actives and decoy molecules and was found to exhibit encouraging statistical attributes (such as AUC > 0.7, BEDROC > 0.5 and EF > 1.0 etc). The model was used to screen the ZINC compound database, from the database, the top best 1375 hits satisfying the pharmacophore model was were docked to MDM2 protein to identify the likely interactions of the compounds as well as their binding affinity with MDM2. Further, druglikeness and pharmacokinetic properties screening on top-ranked compounds with higher binding affinity than reference inhibitors revealed four compounds (ZINC02639178, ZINC38933175, ZINC77969611, and ZINC06752762) with suitable pharmacological properties including low ligand toxicity. Investigation of the dynamic behaviour of each candidate inhibitors in complex with MDM2 via molecular dynamic simulation suggested ZINC02639178 and ZINC06752762 as the most potential inhibitors. Thus, these compounds may emerged as therapeutic option for cancer treatment after extensive in vitro and in vivo studies.

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