scholarly journals Structural Insights into Selective Ligand–Receptor Interactions Leading to Receptor Inactivation Utilizing Selective Melanocortin 3 Receptor Antagonists

Biochemistry ◽  
2017 ◽  
Vol 56 (32) ◽  
pp. 4201-4209 ◽  
Author(s):  
Minying Cai ◽  
Udaya Kiran Marelli ◽  
Blake Mertz ◽  
Johannes G. Beck ◽  
Florian Opperer ◽  
...  
Keyword(s):  
Receptor Antagonists ◽  
Selective Ligand ◽  
Receptor Interactions ◽  
Receptor Inactivation ◽  
Structural Insights

scholarly journals Virus–Receptor Interactions: Structural Insights For Oncolytic Virus Development

2019 ◽  
Vol Volume 8 ◽  
pp. 39-56 ◽  
Author(s):  
Nadishka Jayawardena ◽  
Laura N Burga ◽  
John T Poirier ◽  
Mihnea Bostina
Keyword(s):  
Oncolytic Virus ◽  
Virus Receptor ◽  
Receptor Interactions ◽  
Structural Insights

scholarly journals A quantitative view of strategies to engineer cell-selective ligand binding

2021 ◽  
Author(s):  
Zhixin Cyrillus Tan ◽  
Brian T Orcutt-Jahns ◽  
Aaron S Meyer
Keyword(s):  
Specific Binding ◽  
Cell Types ◽  
Target Cells ◽  
Binding Model ◽  
Combinatorial Explosion ◽  
Model Driven ◽  
Target Populations ◽  
Proposed Model ◽  
Selective Ligand ◽  
Receptor Interactions

Abstract A critical property of many therapies is their selective binding to target populations. Exceptional specificity can arise from high-affinity binding to surface targets expressed exclusively on target cell types. In many cases, however, therapeutic targets are only expressed at subtly different levels relative to off-target cells. More complex binding strategies have been developed to overcome this limitation, including multi-specific and multivalent molecules, creating a combinatorial explosion of design possibilities. Guiding strategies for developing cell-specific binding are critical to employ these tools. Here, we employ a uniquely general multivalent binding model to dissect multi-ligand and multi-receptor interactions. This model allows us to analyze and explore a series of mechanisms to engineer cell selectivity, including mixtures of molecules, affinity adjustments, valency changes, multi-specific molecules and ligand competition. Each of these strategies can optimize selectivity in distinct cases, leading to enhanced selectivity when employed together. The proposed model, therefore, provides a comprehensive toolkit for the model-driven design of selectively binding therapies.

scholarly journals New Insights into Key Determinants for Adenosine 1 Receptor Antagonists Selectivity Using Supervised Molecular Dynamics Simulations

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 732
Author(s):  
Giovanni Bolcato ◽  
Maicol Bissaro ◽  
Giuseppe Deganutti ◽  
Mattia Sturlese ◽  
Stefano Moro
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Binding Site ◽  
Adenosine Receptors ◽  
Water Molecules ◽  
Primary Interest ◽  
Receptor Antagonists ◽  
Dynamics Simulations ◽  
Structural Insights

Adenosine receptors (ARs), like many otherGprotein-coupledreceptors (GPCRs), are targets of primary interest indrug design. However, one of the main limits for the development of drugs for this class of GPCRs is the complex selectivity profile usually displayed by ligands. Numerous efforts have been madefor clarifying the selectivity of ARs, leading to the development of many ligand-based models. The structure of the AR subtype A1 (A1AR) has been recently solved, providing important structural insights. In the present work, we rationalized the selectivity profile of two selective A1AR and A2AAR antagonists, investigating their recognition trajectories obtained by Supervised Molecular Dynamics from an unbound state and monitoring the role of the water molecules in the binding site.

scholarly journals Structural Insights into Human Peroxisome Proliferator Activated Receptor Delta (PPAR-Delta) Selective Ligand Binding

PLoS ONE ◽  
2012 ◽  
Vol 7 (5) ◽  
pp. e33643 ◽  
Author(s):  
Fernanda A. H. Batista ◽  
Daniela B. B. Trivella ◽  
Amanda Bernardes ◽  
Joyce Gratieri ◽  
Paulo S. L. Oliveira ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Delta ◽  
Selective Ligand ◽  
Structural Insights

5-HT4 Receptor Antagonists: Structure-Affinity Relationships and Ligand- Receptor Interactions

2002 ◽  
Vol 2 (6) ◽  
pp. 625-641 ◽  
Author(s):  
M. Lopez-Rodriguez ◽  
B. Benhamu ◽  
M. Morcillo ◽  
M. Murcia ◽  
A. Viso ◽  
...  
Keyword(s):  
Receptor Antagonists ◽  
Receptor Interactions

Attaching Biological Entities to AFM Cantilevers for Molecular Recognition Studies

2007 ◽  
Vol 1025 ◽  
Author(s):  
W. Travis Johnson
Keyword(s):  
High Resolution ◽  
Molecular Interactions ◽  
Structural Information ◽  
Binding Pocket ◽  
Force Microscopy ◽  
Atomic Force ◽  
Selective Ligand ◽  
Dynamic Experiments ◽  
Receptor Interactions ◽  
Biological Entities

AbstractAtomic force microscopy (AFM) is an important tool for high resolution studies in biophysics and mechanical studies directed at biological materials. A strong suit of AFM is its ability to measure hardness/elasticity, nonspecific adhesion or ligand-receptor interactions at the picoNewton scale. Molecular interactions are critical factors in a variety of biological phenomenon; such as the initiation, modulation and termination of DNA replication, transcription, enzyme activity, infection, immune responses, tissue generation, wound healing, cell differentiation, apotopsis and physiological responses from drugs, hormones or toxic agents. Using AFM, scientists can probe and quantify these interactions in their native, liquid environments at physiological pH or perform dynamic experiments in situ by removing or adding ions, solutes and reagents to the sample environment. Bioconjugation chemistry and surface chemistry are crucial because a selective ligand must be immobilized on the tip of an AFM probe so that the AFM can resolve the mechanical force required to separate the ligand and its target. The resulting data can be used to calculate forces of unbinding, derive rate constants and infer structural information about the binding pocket. Biomolecular recognition experiments with AFM can be greatly enhanced through the use of relatively short (~8-10 nm), heterobifunctional, elastic, polyethylene glycol (PEG) linkers to immobilize ligands. Heterobifunctional linkers are used in order to permit their sequential immobilization and bioconjugation, while minimizing undesirable polymerizations or self-conjugation. The linkers have an N-hydroxysuccinimide ester at one end to permit their attachment to aminated silicon or silicon nitride AFM probes. Other reactive functional groups, such as a biotin, maleimide, disulfide, aldehyde, or a photoreactive group reside at the opposite end of the linker to permit the direct or indirect attachment of intact antibodies, Fab fragments, peptides, nucleic acids or other biological entities. The PEG linkers are flexible, so an attached ligand has freedom to diffuse within a defined volume of space and approach the binding site in a thermodynamically favorable manner. PicoTREC, an accessory for the Agilent AFM, uses ligand-PEG modified cantilevers to generate a topography image and a recognition image of biomolecular interactions. As the modified cantilever gently oscillates at defined amplitude, it is scanned across a sample and PicoTREC converts the information derived from ligand-receptor interactions into a high resolution, nanometer-scale map. Consequently, the locations of discrete molecular interactions can be easily determined and compared with a topography image of the sample.

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