The capsaicin receptor TRPV1 (transient receptor potential vanilloid 1) has been an object of intense interest for pharmacological development on account of its critical role in nociception. In the course of structure activity analysis, it has become apparent that TRPV1 ligands may vary dramatically in the rates at which they interact with TRPV1, presumably reflecting differences in their abilities to penetrate into the cell. Using a fast penetrating agonist together with an excess of a slower penetrating antagonist, we find that we can induce an agonist response of limited duration and, moreover, the duration of the agonist response remains largely independent of the absolute dose of agonist, as long as the ratio of antagonist to agonist is held constant. This general approach for limiting agonist duration under conditions in which absolute agonist dose is variable should have more general applicability.
Capsaicin ; Ligands ; Nociception

To learn the differences between the structure-activity relationship and molecular vibration-activity relationship in the ligand-receptor interaction of the histamine receptor, 47 ligands of the histamine receptor were analyzed by structural similarity and molecular vibrational frequency patterns. The radial tree that was produced by clustering analysis of molecular vibrational frequency patterns shows its potential for the functional classification of histamine receptor ligands.
Histamine ; Ligands ; Receptors, Histamine ; Structure-Activity Relationship

Toll-like receptors (TLRs) are pattern recognition receptors (PRRs) expressed in a wide spectrum of cell types that recognize distinctive ligands and subsequently activate adaptive immune responses. TLR ligands are considered a promising target for development of immunomodulatory agents. Extensive clinical investigations are currently underway to develop TLR ligands-based non-specific immunostimulants and vaccine adjuvants. It has been well accepted that cancer cells develop a strategy to avoid host immune responses by producing inhibitory molecules. In addition, tumor-associated antigens are often not strong enough to induce effective anti-cancer immune responses. In this context, immunostimulants or adjuvants are critically required for more effective cancer immunotherapies. Here, we discuss recent progresses in the field of cancer immunotherapy under special emphasis on the TLR ligands as a component of immunostimulatory agents.
Adjuvants, Immunologic ; Immunotherapy ; Ligands ; Receptors, Pattern Recognition ; Toll-Like Receptors

Estrogen receptors (ERs) are members of nuclear receptors and related to several diseases such as cancer, inflammation and osteoporosis. ERs have two forms, ERα and ERβ, which have different functions and organism distributions. Compounds selectively targeting ERβ can regulate important physiological functions and avoid the side effects caused by targeting ERα. Therefore, selective ERβ ligands have received considerable research interest in recent years. In this article, different kinds of selective ERβ ligands were summarized and their structure-activity relationships were also analyzed.
Estrogen Receptor beta ; chemistry ; Humans ; Ligands ; Structure-Activity Relationship

G protein-coupled receptors (GPCRs) mediate signal transduction via G protein or β-arrestin. Several biased ligands and receptors that preferentially signal through either G protein- or β-arrestin-mediated pathways have been identified. These discoveries have redefined the classical GPCR signaling paradigm. Distinct ligand-receptor binding sites might be one of the main reasons for biased signal transduction. It is posited that multiple active conformations of receptors lead to distinct kinase phosphorylation patterns on C terminus of receptors. Phosphorylation patterns decide which signal pathway will be transduced. The biased signal pathway transduction has been found in more than 40 GPCRs till now. A few of them have been found involved in fine-regulation of physiological processes. However, most others still need further investigation. The biased ligands may be developed as tools for understanding the basic physiology of GPCR, and, potentially and most importantly, as fine-tuned therapeutics that maximize beneficial effects and minimize adverse or unwanted effects. These studies will provide new insights into new drug discovery.
Ligands ; Phosphorylation ; Receptors, G-Protein-Coupled ; Signal Transduction

Estrogen receptor (ER) and progesterone receptor (PR) are two important members of steroid receptors family, an evolutionarily conserved family of transcription factors. Upon binding to their ligands, ER and PR enter cell nucleus to interact with specific DNA element in the context of chromatin to initiate the transcription of diverse target genes, which largely depends on the timely recruitment of a wide range of cofactors. Moreover, the interactions between steroid hormones and their respective receptors also trigger post-translational modifications on these receptors to fine-tune their transcriptional activities. Besides the well-known phosphorylation modifications on tyrosine and serine/threonine residues, recent studies have identified several other covalent modifications, such as ubiquitylation and sumoylation. These post-translational modifications of steroid receptors affect its stability, subcellular localization, and/or cofactor recruitment; eventually influence the duration and extent of transcriptional activation. This review is to focus on the recent research progress on the transcriptional activation of nuclear ER and PR as well as their physiological functions in early pregnancy, which may help us to better understand related female reproductive diseases.
Ligands ; Phosphorylation ; Receptors, Estrogen ; Receptors, Progesterone ; Sumoylation ; Transcriptional Activation

The emerging of network pharmacology and polypharmacology forces the scientists to recognize and explore new mechanisms of existing drugs. The drug target prediction can play a key significance on the elucidation of the molecular mechanism of drugs and drug reposition. In this paper, we systematically review the existing approaches to the prediction of biological targets of small molecule based on chemoinformatics, including ligand-based prediction, receptor-based prediction and data mining-based prediction. We also depict the strength of these methods as well as their applications, and put forward their developing direction.
Computational Biology ; Data Mining ; Drug Delivery Systems ; Drug Design ; Ligands

Recently, along with the thorough investigation on the gene and molecular biology of peroxisome proliferators activated receptorgamma (PPARgamma), the therapeutic effects of PPARgamma ligand and its potential mechanism were gradually recognized. PPARgamma will probably become a new target of oncotherapy and is now extensively followed by researchers. This review focuses the advances of study on PPARgamma distribution in tissue, its function, its ligand in relationship with hematologic malignancies including acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, lymphoma, multiple myeloma and so on.
Hematologic Neoplasms ; metabolism ; pathology ; Humans ; Ligands ; PPAR gamma ; metabolism

The interaction between ephrin ligands (efn) and their receptors (Eph) is capable of inducing forward signaling, from ligand to receptor, as well as reverse signaling, from receptor to ligand. The ephrins are widely expressed in many tissues, where they mediate cell migration and adherence, properties that make the efn-Eph signaling critically important in establishing and maintaining tissue boundaries. The efn-Eph system has also received considerable attention in skeletal tissues, as ligand and receptor combinations are predicted to mediate interactions between the different types of cells that regulate bone development and homeostasis. This review summarizes our current understanding of efn-Eph signaling with a particular focus on the expression and functions of ephrins and their receptors in bone.
Bone Development ; Cell Movement ; Ephrins ; Homeostasis ; Ligands ; Osteoblasts ; Osteoclasts

Translocator protein 18 kDa (TSPO) is a mitochondrial protein highly expressed on reactive microglia and astrocytes, and is considered as a biomarker for neurodegeneration and brain damage, especially neuroinflammation. Toll-like receptors (TLRs) are closely related with inflammatory responses of microglia and astrocytes and these signaling pathways regulate neuroinflammation. Previous reports have identified the anti-inflammatory effects of TSPO ligands, however study of their effects in relation to the TLR signaling was limited. Here, we investigated the effects of five representative TSPO ligands on microglia and astrocytes following activation by various TLR ligands. Our results show that TSPO ligands reduce the pro-inflammatory response elicited by the TLR ligands with more profound effects on microglia than astrocytes.
Astrocytes* ; Brain ; Ligands* ; Microglia* ; Mitochondrial Proteins ; Toll-Like Receptors