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Finding a Target
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
Cell signalling processes allow the cells that make up multicellular organism to communicate with one another; be it their neighbours or distant cells elsewhere in the body. Any given cells may be exposed to hundreds of signals, not all of them relevant to its particular function. In order to perform their specific role in the body, each cell is programmed to respond to specific combinations of signalling molecules. Furthermore, different cells respond differently to the same chemical signals. This means that the behaviour of cells can be controlled in highly specific ways. These signalling molecules generate a response by binding to cell surface receptor proteins, which act as signal transducers, where the binding of the signalling ligand induces an intracellular response that alters the behaviour of the target cell. There are three known classes of cell surface receptor, defined by the mechanism of transduction used. Ion-channel-linked receptors are those involved in the rapid synaptic signalling between neurones during an action potential (nerve impulse), mediated by neurotransmitters. G-protein-linked receptors indirectly regulate the activities of target proteins bound separately to the plasma membrane, for example enzymes or channel proteins. The mediator for this process is called “G protein”, which binds to the receptor, and then upon binding of the signalling molecule to the receptor, becomes activated, and then departs to bind to, and activate, the target enzyme or channel protein. The third type of receptor are enzyme-linked receptors, which become activated by a signalling molecule and prompted into acting as an enzyme.
Protein Function As Cell Surface And Nuclear Receptor In Human Diseases
Published in Debarshi Kar Mahapatra, Sanjay Kumar Bharti, Medicinal Chemistry with Pharmaceutical Product Development, 2019
Urmila Jarouliya, Raj K. Keservani
The receptors are the protein molecule, usually found in the cells’ plasma membrane; facing extracellular (cell surface receptors), cytoplasmic (cytoplasmic receptors), or in the nucleus (nuclear receptors). The chemical signals such as hormones, cytokines, growth factors, enzyme or any ligand bind to a receptor that is triggering changes in the function of the cellular activity by means of various signaling pathways, this process is called signal transduction. There are several receptor components present in the cell and can be classified into the following categories: G protein-coupled receptors: also known as seven transmembrane G-protein receptor that includes the receptors for several hormones and slow transmittersReceptor tyrosine kinase and enzyme-linked receptor: plasma membrane receptors that are also enzymes. When one of these receptors is activated by its extracellular ligand, catalyzes the production of an intracellular second messenger ex: the insulin receptorNuclear receptors: When binding to their specific ligand (such as the hormone), alter the rate at which specific genes are transcribed and translated into cellular proteins. Steroid and thyroid hormone receptors are examples of such receptors.Ionotropic receptors: these are gated-ion channels in the plasma membrane that open and close in response to the binding of chemical ligands such as acetylcholine (nicotinic) and gamma-aminobutyric acid (GABA) and activation of these receptors, results in changes in ion movement across the membrane.
Signal transduction and exercise
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Brendan Egan, Adam P. Sharples
In Step 2, perturbations to homeostasis are linked to subsequent signal transduction pathways by a panoply of sensor proteins found within cells and on cell membranes. For the purposes of this model, these sensor proteins can be further divided into small molecule sensors, transmembrane receptorsand other cellular sensors/receptors. Small molecule sensors are proteins that contain domains capable of binding molecules such as Ca2+, or AMP and ADP, and this enables the cell to sense changes in the concentration of these molecules through sensor proteins such as CaM and AMPK, respectively (Table 7.1). Transmembrane (or cell surface) receptors are typically single proteins (e.g. G protein-coupled receptors), enzyme-linked receptors (e.g. receptor tyrosine kinases) or protein complexes (e.g. ligand-gated ion channels) that are embedded in the cell membrane in a transmembrane orientation that allows for the transduction of signals arising outside the cell into processes inside the cell, i.e. coupling external signals to internal regulation of metabolism. Activation of a receptor occurs when a ligand such as a hormone, e.g. insulin, or a neurotransmitter, e.g. acetylcholine, binds to the relevant receptor on the cell surface, which, in turn, leads to a cascade of downstream events. A subclass of hormone receptors are receptors for steroid hormones such as testosterone, which typically reside in the intracellular (cytoplasmic) space and are referred to as nuclear receptors. These receptors, such as the AR, typically have a strong influence on gene expression due to their function as transcription factors with an ability to bind directly to DNA and thereby influence transcription of target genes. Other cellular sensors/receptors typically include sensors of physical properties rather than the presence of metabolites or ligands, with examples being sensors of stretch or load through a cell, or of the physical interactions between cells.
Dual potent c-Met and ALK inhibitors: from common feature pharmacophore modeling to structure based virtual screening
Published in Journal of Receptors and Signal Transduction, 2020
Somayeh Pirhadi, Tahereh Damghani, Mohammad Sadegh Avestan, Shahrzad Sharifi
Receptor tyrosine kinases (RTKs), the biggest identified group of enzyme-linked receptors, play fundamental roles in cellular processes and disease pathogenesis. RTK signal transduction pathways map an extensive spectral range of functions, including regulation of cellular proliferation, migration, metabolism, differentiation, and survival [1]. Dysregulation of RTK signaling leads to numerous human diseases, especially cancer. There are four principal mechanisms of RTK dysregulation in human cancers: point mutation, amplification, and rearrangement of the corresponding genes [2]. However, due to the critical roles of aberrant signaling from the receptor tyrosine kinase in cancer, both Met (mesenchymal epithelial transition factor) and ALK (anaplastic lymphoma kinase) receptor tyrosine kinases are attractive targets of cancer therapy [3]. c-Met is a type of receptor tyrosine kinase that is expressed on the surfaces of various epithelial cells and its ligand is HGF/SF (ligand hepatocyte growth factor/scatter factor) [4,5]. c-Met over-expression and mutation are correlated with tumorigenesis, metastasis, poor prognosis, and drug resistance [6,7] which occur in a variety of human tumor types and these events are closely related to the aberrant activation of the HGF/c-Met signaling pathway [8].
Exploring structural features of EGFR–HER2 dual inhibitors as anti-cancer agents using G-QSAR approach
Published in Journal of Receptors and Signal Transduction, 2019
Shehnaz Fatima, Subhash Mohan Agarwal
According to the dual model, it was concluded that, (a) at R1 position, decreasing second alpha modified shape index substitution; (b) at R2 position, the presence of chlorine atom and lower value of EpsilonR; (c) at R3 position, decreasing first alpha modified shape index substitution; and (d) at R4 position, increasing electronegative character substitution and higher index of the saturated carbon; are ideal for increasing the inhibitory potency of the molecules. In addition, interaction descriptors were studied which revealed that the presence of Sum(R4-ElectronegativityCountEH, R2-T_T_Cl_0) is required for the enhancement of the dual inhibitor bioactivity of molecules. We also analyzed the behavior of most and least active molecules and established that the most active compounds retain properties, which are essential to optimize the inhibitory activity against both the enzyme linked receptors. Thus, the generated dual model can be used to design and predict the inhibitory activity of new pyrrolo[3,2-d]pyrimidine based anti-cancer compounds as dual inhibitors against the EGFR and HER2 enzyme linked receptors.
Brain Environment Interactions: Stress, Posttraumatic Stress Disorder, and the Need for a Postmortem Brain Collection
Published in Psychiatry, 2022
Elizabeth Osuch, Robert Ursano, He Li, Maree Webster, Chris Hough, Carol Fullerton, Gregory Leskin
Tyrosine kinase receptor: n. Any group of enzyme–linked receptors of the transferase class that catalyze the phosphorylation of tyrosine residues in specific membrane vesicle associated proteins. The enzyme activity is present in certain membrane proteins and is a product of some oncogenes.