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<p>M<sub>3</sub> subtype of muscarinic acetylcholine receptors (mAChRs) is a very important drug target validated for irritable bowel syndrome (IBS), over active bladder (OAB), and chronic obstructive pulmonary disease (COPD). The M<sub>2</sub> subtype has high sequence and structural similarity with M<sub>3</sub>. This makes it difficult to design selective inhibitors for M<sub>3</sub> subtype. To address this problem, a three-dimensional quantitative structure–activity relationship (3D-QSAR) pharmacophore model was generated to estimate M<sub>2</sub> specific inhibitory constant (<i>K</i><sub><i>i</i></sub>). The predictions were compared with a reported 3D-QSAR M<sub>3</sub> pharmacophore model to calculate M<sub>3</sub>/M<sub>2</sub> selectivity ratio. This double-pharmacophore workflow was validated over known M<sub>3</sub> antagonists. It was then applied to virtually screen a focused PubChem library with ‘<i>piperazine–triazole</i>’ scaffold. The top-ranked M<sub>3</sub> selective candidates (10673583 and 46934496) were further studied for their molecular interactions at the orthosteric binding pocket of both M<sub>2</sub> and M<sub>3</sub> in silico, such as Molecular Mechanics/Poisson–Boltzmann Surface Area (MM/PBSA) and, Molecular Mechanics/Generalized Born Surface Area (MM/GBSA). The results predicted strong hydrogen bonding along with hydrophobic, hydrophilic, and π–π interactions of the M<sub>3</sub> receptor–ligand complexes over M<sub>2</sub>.</p> Graphical abstract <p></p>

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Development of a double-pharmacophore workflow for screening subtype-selective M3 muscarinic acetylcholine receptor antagonists

  • 期刊论文

  • 发表日期：

    2026年6月28日

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  • Sirat Kaur Gill,
  • Sandhya Chahal,
  • Shyam Sundar Sarkar,
  • Tara Yadava,
  • Jayant Sindhu,
  • Badri N. Acharya

摘要

M3 subtype of muscarinic acetylcholine receptors (mAChRs) is a very important drug target validated for irritable bowel syndrome (IBS), over active bladder (OAB), and chronic obstructive pulmonary disease (COPD). The M2 subtype has high sequence and structural similarity with M3. This makes it difficult to design selective inhibitors for M3 subtype. To address this problem, a three-dimensional quantitative structure–activity relationship (3D-QSAR) pharmacophore model was generated to estimate M2 specific inhibitory constant (Ki). The predictions were compared with a reported 3D-QSAR M3 pharmacophore model to calculate M3/M2 selectivity ratio. This double-pharmacophore workflow was validated over known M3 antagonists. It was then applied to virtually screen a focused PubChem library with ‘piperazine–triazole’ scaffold. The top-ranked M3 selective candidates (10673583 and 46934496) were further studied for their molecular interactions at the orthosteric binding pocket of both M2 and M3 in silico, such as Molecular Mechanics/Poisson–Boltzmann Surface Area (MM/PBSA) and, Molecular Mechanics/Generalized Born Surface Area (MM/GBSA). The results predicted strong hydrogen bonding along with hydrophobic, hydrophilic, and π–π interactions of the M3 receptor–ligand complexes over M2.

Graphical abstract