Design of New Imaging Agents Using Positron-Emitting Radionuclides as the Reporter
Martin G. Pomper, Juri G. Gelovani, Benjamin Tsui, Kathleen Gabrielson, Richard Wahl, S. Sam Gambhir, Jeff Bulte, Raymond Gibson, William C. Eckelman in Molecular Imaging in Oncology, 2008
Mariani et al. have recently commented on various radiolabeled peptides that are targeted to tumors expressing upregulated receptor density. They outline the use of glucagon-like peptide-1 (GLP-1), various cholecystokininrelated peptides (CCK-A and CCK-B/gastrin, gastrin-1, gastrin-releasing peptide), vascular endothelial growth factor (VDGF, in particular VEGFR-2 and neuropilin-1), and amino acids arginine-glycine-aspartic (RGD) analogs targeted at the αvβ3 integrin receptor involved in angiogenesis. The authors outline their design parameters as predictors of successful clinical use as (a) receptor density on the target (particularly if overexpressed in a variety of cancers), (b) affinity of the ligand for receptor binding, (c) specific activity of the labeled ligand, (d) plasma half-life (short to intermediate), (e) route of metabolic degradation or excretion (renal clearance preferred), (f) ex vivo counted % ID/g tumor in adequate animal models, (g) maximum tumor-to-background ratio achievable in vivo and time at which this is achieved, and (h) time course of the tumor-to-background ratios between an early (e.g., 2 hours after injection) and a late time point (e.g., 24 hours), expressed as the ratio (62).
Simple Receptor-Ligand Interactions
John C. Matthews in Fundamentals of Receptor, Enzyme, and Transport Kinetics, 2017
Plotting BL vs. log [L] spreads out the information at low concentrations of L and compresses the information at high concentrations of L. This allows us to see in more detail the features of the relationship between BL and [L]. One striking feature of the relationship is that only within a relatively narrow range of L concentrations is there any substantial influence of [L] on the amount of RL. A second feature is that the KD is at the exact center of this rather narrow concentration range. Within two log units (or 100-fold) of [L] above and below the KD value we go from 99% of BLmax to 1% of BLmax. Within these four orders of magnitude of [L] (a 10,000-fold concentration range) practically all the influence of ligand concentration on receptor occupancy is accomplished. Outside of this concentration range there is very little effect of changes in the ligand concentration on receptor occupancy. Thus, the KD value defines the effective ligand concentration range for interaction with the receptor.
Nanocarriers as an Emerging Platform for Cancer Therapy
Lajos P. Balogh in Nano-Enabled Medical Applications, 2020
It is generally known that higher binding affinity increases targeting efficacy. However, for solid tumours, there is evidence that high binding affinity can decrease penetration of nanocarriers due to a ‘binding-site barrier’, where the nanocarrier binds to its target so strongly that penetration into the tissue is prevented [16, 21]. In addition to enhanced affinity, multivalent binding effects (or avidity) may also be used to improve targeting. The collective binding in a multivalent interaction is much stronger than monovalent binding. For example, dendrimer nanocarriers conjugated to 3–15 folate molecules showed a 2,500–170,000-fold enhancement in dissociation constants (KD) over free folate when attaching to folate-binding proteins immobilized on a surface. This was attributed to the avidity of the multiple folic acid groups on the periphery of the dendrimers [22].
Virtual screening for potential inhibitors of β(1,3)-D-glucan synthase as drug candidates against fungal cell wall
Published in Journal of Drug Assessment, 2020
Zinat Farhadi, Tayebeh Farhadi, Seyed MohammadReza Hashemian
In order to select the leads as hopeful drug candidates, “binding energy” between each molecule (ligand) and the receptor can be a suitable criterion and calculated through docking analysis20. Overall, evaluation of some factors such as “binding energy” and “number of hydrogen bonds” between ligands and their receptors has been interpreted as a computational filtering method to limit the number of drug candidates for experimental analysis16. The degree of ligand-receptor binding refers to the binding affinity. The energy released due to the bond formation or, rather, interaction of the ligand and protein is termed in the form of binding energy. The free energy of a favorable reaction is negative. Lesser the binding energy, the better is the binding of the ligand and protein16,21–27. In this study, the virtual screening software was employed to screen a library of agents against the protein receptor, 1,3-β-D-glucan synthase. The results of this study may be promising in the field of discovering and designing novel drug candidates against fungal infections.
The enigmatic nature of the triggering receptor expressed in myeloid cells -1 (TLT- 1)
Published in Platelets, 2021
Siobhan Branfield, A. Valance Washington
Key to understanding the function of any receptor is the identification of its ligand. In our early studies we proposed fibrinogen as a ligand of TLT-1 and suggested that during platelet aggregation, TLT-1 cross-links extracellular fibrinogen, stabilizing higher-order platelet aggregates [18]. In this study, lysates generated from purified human platelets were applied to AminoLink columns preloaded with either sTLT-1 or sTREM-1. This approach revealed specific binding of 3 proteins with molecular masses between 50 and 80 kDa on a Coomassie stained gel. Mass spectroscopy identified these proteins as the α, β, and γ chains of fibrinogen. To confirm these findings, fibrinogen was also eluted from His-tagged TLT-1 but not TREM-1 bound to nickel columns and resolved by PAGE in either native or reduced conditions. Consistent with disulfide-linked multimers of fibrinogen, TLT-1 column specifically bound a high molecular weight complex that when reduced resolved into the same 3 bands detected with AminoLink columns. Immunoblotting with anti-fibrinogen confirmed the identity of these TLT-1–interacting proteins as fibrinogen. This was further supported by ELISA, confirming fibrinogen as a TLT-1 ligand. While the identification of fibrinogen as a ligand was expected to bring answers, it only generated larger questions.
Integration of network pharmacology and intestinal flora to investigate the mechanism of action of Chinese herbal Cichorium intybus formula in attenuating adenine and ethambutol hydrochloride-induced hyperuricemic nephropathy in rats
Published in Pharmaceutical Biology, 2022
Na Li, Mukaram Amatjan, Pengke He, Boheng Zhang, Xianyan Mai, Qianle Jiang, Haochen Xie, Xiaoni Shao
The PDB ID of the core target proteins obtained above was searched in UniProt. The three-dimensional structure files of core target proteins were retrieved and downloaded in PBD format via the RSCB PBD database (https://www.rcsb.org/), and the MOL2 structure of the core components was downloaded from the TCMSP database. The downloaded target proteins were preprocessed using AutoDockTools-1.5.6 and PyMOL software for removing water molecules, separating proteins, adding non-polar hydrogens, calculating the Gasteiger charges for the structure, and saving them as PDBQT files (Morris et al. 2009). AutoDock is a prevalent receptor-ligand docking simulation programme. In this study, the target protein was the receptor and the active ingredient was the ligand. AutoDock was also used to evaluate the binding affinity of the protein to the ligand and to choose the lowest energy conformation in the docking simulation (Bitencourt-Ferreira et al. 2019). Ultimately, Autodock Vina was adopted for molecular docking, and it is commonly believed that the lower the binding energy of the receptor to the ligand, the higher the affinity and the greater the likelihood of binding occurring. The conformation with the lowest affinity was opted as the superior docking conformation and visualized in Pymol.
Related Knowledge Centers
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