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• W202359470 abstract "G protein-coupled receptors (GPCRs) constitute a very large family of heptahelical, integral membrane proteins that mediate a wide variety of physiological processes, ranging from the transmission of the light and odorant signals to the mediation of neurotransmission and hormonal actions. GPCRs are dysfunctional or deregulated in several human diseases and are estimated to be the target of more than 40% of drugs used in clinical medicine today. The crystal structures of rhodopsin and the recent published crystal structures of beta-adrenergic receptors and human A2A Adrenergic Receptor provide the information of the three-dimensional structure of GPCRs, which supports homology modeling studies and structure-based drug-design approaches. Rhodopsin-based homology modeling has represented for many years a widely used approach to built GPCR three-dimensional models. Structural models can be used to describe the interatomic interactions between ligand and receptor and how the binding information is transmitted through the receptor. Both agonist and antagonist like states can be described by several different conformational receptor states depending on the nature of both ligand and receptor. Considering different complementarities, we might explore different conformations of the same pharmacological state. We investigated the molecular pharmacology of adenosine receptors and, in particular, the human A3 adenosine receptor (hA3AR) by using an interdisciplinary approach to speed up the discovery and structural refinement of new potent and selective hA3AR antagonists. Human A3AR belongs to adenosine receptors family of GPCRs, which consists of four distinct subtypes: A1, A2A, A2B, A3 that are ubiquitously expressed in the human body.The hA3AR, which is the most recently identified adenosine receptor, is implicated in a variety of important physiological processes. Activation of A3ARs increases the release of inflammatory mediators, such as histamine from rodent mast cells, and it inhibits the production of tumor necrosis factor-alpha. The activation of the hA3AR seems to be involved in immunosuppression and in the response to ischemia of the brain and heart. Agonists or antagonists of A3ARs are potential therapeutic agents for the treatment of ischemic and inflammatory diseases.The first model of human A3AR has been built using a conventional rhodopsin-based homology modeling approach. The model has been used to probe atomic level specific interactions, detected using site-directed mutagenesis analysis.The rhodopsin-based model of the hA3AR in its resting state (antagonist-like state) has been revisited, taking into account a novel strategy to simulate the possible receptor reorganization induce by the antagonist-binding. We called this new strategy ligand-based homology modeling (LBHM). It is an evolution of a conventional homology modeling algorithm: any selected atoms will be included in energy tests and in minimization stages of the modeling procedure. Ligand-based option is very useful when one wishes to build a homology model in the presence of a ligand docked to the primary template. Starting from the conventional rhodopsin-based homology model and applying our ligand-based homology modeling implementation we can generate other antagonist-like conformational states of hA3AR in which the ligand recognition cavity is expanded. Using different antagonist-like conformational states, we are able to rationalize the observed activities for all the compounds analyzed. Many severe analysis concerning false-positives and false-negatives situations are usually conducted. To strictly validate this methodology as novel tool to address the multi-conformational space of GPCRs, we have analyzed different classes of known human A3 antagonists in the corresponding putative ligand binding site: for example triazoloquinoxalin-1-one derivatives, arylpyrazolo-quinoline derivatives and pyrazolo-triazolo-pyrimidines derivatives. These studies led to the identification of groups for every class of antagonists that, introduced one by one in a suitable position, afford high hA3AR affinity and good selectivity. Starting from these binding requirements, we decided to perform an in silico molecular simplification approach to identify a suitable fragmentation route of the 4-amino-triazoloquinoxalin-1-one scaffold and explore which of the structural features were essential to guarantee efficient ligand-receptor recognition. With the availability of new three dimensional templates different from rhodopsin, we built new models of hA3AR. All the models were used for a molecular dynamic simulation in a POPC bilayer to investigate the topological fluctuation of the binding pocket." @default.
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• W202359470 date "2009-01-30" @default.
• W202359470 modified "2023-09-24" @default.
• W202359470 title "G Protein-Coupled Receptors as Potential Drug Target: From Receptor Topology to Rational Drug Design, an in-silico Approach" @default.
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