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Information × Registration Number 0224U031767, 0123U102103 , R & D reports Title Rational design of muscarinic acetylcholine receptor type 2 activators as potential components of acute myocardial infarction and myocardial wound therapy popup.stage_title Head Nyporko Oleksii Yu., Кандидат біологічних наук Registration Date 13-06-2024 Organization Taras Shevchenko National University of Kyiv popup.description2 The spatial structure of the full-length mAChRs M2 receptor was reconstructed, and 5 potential sites for the specific binding of low-molecular-weight compounds were identified on its surface. The most promising of these is the orthosteric binding site for the Iperoxo-independent mAChRs agonist, as well as a number of non-selective mAChRs antagonists (inhibitors). In addition, the allosteric binding site, similar to the orthosteric one, serves as a binding site for some non-selective mAChRs activators, in particular, LY2119620. Both sites are located within the protein directly above each other. These sites were used for further virtual screening of a collection of artificially synthesised organic compounds, as well as some naturally occurring compounds, in particular, quercetin, and several nanomaterials. Among the substances with the best scoring function values, 16 organic compounds were selected, and their thermodynamic parameters were determined. The corresponding values of the free binding energies ranged from -6.733 to -10.867 kcal/mol. Further, the pharmacological properties of the compounds were determined using a model of multicellular smooth muscle preparations of the rat intestine. It was found that all 16 studied substances enhance caecum contractions, and 2 compounds (146539 and 248008) are significantly more active than others. Thus, compound 146539 (10-9 - 10-6 M) causes activation of acetylcholine-induced caecum contractions. In concentrations of 10-8-10-6 M, it inhibits spontaneous contractions and belongs to the class of substances that we identified as selective antagonists of another subtype of mAChRs, namely M3, which makes this compound promising for further studies of switching the activity types of low-molecular weight compounds. It was shown that compound 248008 effectively enhanced spontaneous contractions of caecum during prolonged exposure (30 and 60 min). Compound 248008 did not lose its efficacy during prolonged in vitro application.   Product Description popup.authors Volodymyr V. Burianov Voiteshenko Ivan S. Hrebinchuk Veronika R. Drahan Anatolii I. Sukhopara Serhii V. Olha V. Tsymbaliuk Chervetsova Veronika H. popup.nrat_date 2024-06-13 Close