Related Experiment Video
Updated: Aug 6, 2026
07:41
A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
Structural basis for the interaction of CCR5 with a small molecule, functionally selective CCR5 agonist
Yuji Saita1, Eiichi Kodama, Masaya Orita
1Molecular Medicine Research Laboratories, Institute for Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan. yuuji.saita@jp.astellas.com
Journal of Immunology (Baltimore, Md. : 1950)
|August 22, 2006
Summary
A novel CCR5 agonist, YM-370749, inhibits HIV-1 replication by down-modulating CCR5 without causing inflammation. This discovery offers a new strategy for developing selective anti-HIV-1 drugs.
Area of Science:
- Virology
- Immunology
- Medicinal Chemistry
Background:
- Chemokine receptor CCR5 is a key target for HIV-1 drug development.
- Existing CCR5 ligands inhibit HIV-1 but cause inflammation, limiting clinical use.
- Individuals lacking CCR5 expression are resistant to HIV-1 infection.
Purpose of the Study:
- To identify and characterize a novel, functionally selective CCR5 agonist.
- To investigate the potential of YM-370749 as an anti-HIV-1 agent.
- To elucidate the structural basis of CCR5 activation by selective agonists.
Main Methods:
- Molecular docking studies using a 3D CCR5 model.
- Binding and functional assays with CCR5 mutants.
- Assessment of YM-370749's effect on HIV-1 replication and CCR5 modulation.
Main Results:
- YM-370749 selectively down-modulates CCR5 from the cell surface.
- YM-370749 inhibits HIV-1 replication without inducing chemotaxis.
- Key amino acid residues involved in YM-370749 binding to CCR5 were identified.
Conclusions:
- YM-370749 represents a novel class of functionally selective CCR5 agonists.
- This compound offers a promising therapeutic strategy for HIV-1 infection.
- The study provides a structural framework for designing new anti-HIV agents.
More Related Videos
Related Concept Videos
01:25Drug-Receptor Interaction: Agonist
Agonists are drugs that interact with specific receptors in the body to produce a biological response. When an agonist binds to a receptor, it activates or enhances the receptor's function, leading to physiological effects. The interaction between agonist drugs and receptors is crucial for their therapeutic action in various medical treatments.
Agonists can bind to receptors in different ways. Some agonists bind directly to the receptor's active site, mimicking the endogenous ligand's action.
Agonists can bind to receptors in different ways. Some agonists bind directly to the receptor's active site, mimicking the endogenous ligand's action.
01:29The Two-State Receptor Model
The two-state receptor model explains a drug's interaction with receptors, such as G protein-coupled receptors and ligand-gated ion channels, to induce or inhibit a biological response. When no natural ligands are present, a receptor exists in an equilibrium of inactive (Ri) and active (Ra) conformations. The inactive form does not produce a response, while the active form generates a basal effect known as constitutive activity.
The binding affinity of a drug determines its interaction with one...
The binding affinity of a drug determines its interaction with one...
01:29Drug-Receptor Interactions
Drug-receptor interaction describes the binding of receptors by drugs, but not all drug-receptor interactions result in activation and tissue response. For instance, the binding of agonists activates the receptor to generate a cellular reaction, while antagonists bind to receptors without causing their activation.
Several parameters, such as the drug's affinity for its receptor and its efficacy, which is its ability to activate the receptor, determine the drug's effect on the tissue.
Several parameters, such as the drug's affinity for its receptor and its efficacy, which is its ability to activate the receptor, determine the drug's effect on the tissue.
01:16Adrenergic Agonists: Chemistry and Structure-Activity Relationship
Adrenergic agonists' structure-activity relationship (SAR) determines their selectivity and efficacy. These agonists comprise a phenylethylamine moiety with an aromatic ring and an ethylamine side chain.
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of the aromatic...
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of the aromatic...
01:25Drug-Receptor Bonds
Drug-receptor bonds are formed through various chemical forces when drugs interact with target cells. Covalent bonds, strong and irreversible, are exemplified by DNA-alkylating anticancer agents that inhibit cell division. However, such irreversible drug binding lacks selectivity and can modify the DNA of the surrounding healthy cells. Covalent binding often contributes to tissue toxicity, as seen with chloroform and paracetamol metabolites binding to the liver, causing hepatotoxicity.
In...
In...
01:28Drug-Receptor Interaction: Antagonist
An antagonist is a drug that binds strongly to a receptor without activating it. An antagonist prevents other molecules, such as neurotransmitters or hormones, from binding to the receptor and triggering a cellular response. Such interaction effectively hinders the normal physiological processes mediated by the receptor, resulting in various pharmacological effects depending on the specific receptor targeted.
Antagonists can be classified as competitive or noncompetitive based on their...
Antagonists can be classified as competitive or noncompetitive based on their...