Computer-aided design of muscarinic acetylcholine receptor M3 inhibitors: Promising compounds among trifluoromethyl containing hexahydropyrimidinones/thiones

  • Mol Inform. 2023 Aug;42(8-9):e2300006. doi: 10.1002/minf.202300006.
Alex Nyporko  1 ,  Olga Tsymbalyuk  1 ,  Ivan Voiteshenko  1 ,  Sergiy Starosyla  2 ,  Mykola Protopopov  3 ,  Volodymyr Bdzhola  4
Affiliations
  • 1. Taras Shevchenko National University of Kyiv, Kyiv, 01033, Ukraine.
  • 2. Receptor.AI Inc., 20-22 Wenlock Road, London, N1 7GU, United Kingdom.
  • 3. Chemspace LLC, Kyiv, Ukraine.
  • 4. Institute of Molecular Biology and Genetics, NAS of Ukraine, Kyiv, 03143, Ukraine.
PMID: 37293808 DOI: 10.1002/minf.202300006
Abstract

The new high selective mAChRs M3 inhibitors with IC50 in nanomolecular ranges, which can be the prototypes for effective COPD and asthma treatment drugs, were discovered with computational approaches among trifluoromethyl containing hexahydropyrimidinones/thiones. Compounds [6-(4-ethoxy-3-methoxy-phenyl)-4-hydroxy-2-thioxo-4-(trifluoromethyl)hexahydropyrimidin-5-yl]-phenyl-methanone (THPT-1) and 5-benzoyl-6-(3,4-dimethoxyphenyl)-4-hydroxy-4-(trifluoromethyl)hexahydropyrimidin-2-one (THPO-4) have been proved to be a highly effective (with IC50 values of 1.62 ⋅ 10-7 M and 3.09 ⋅ 10-9 M, respectively) at the same concentrations significantly competitive inhibit the signal conduction through mAChR3 in comparison with ipratropium bromide, without significant effect on mAChR2, nicotinic cholinergic and adrenergic receptors.

Keywords
airway smooth muscle; chronic obstructive pulmonary disease (COPD); computer modeling; mAChRs; molecular docking; muscarinic acetylcholine receptor inhibitors; rational drug design; virtual screening.