Novel γ-Butyrolactone Derivatives as Muscarinic Receptor Antagonists: Pharmacophore Elucidation and Docking Analyses

Abstract

Our efforts in design and development of novel muscarinic acetylcholine receptor (mAChR) antagonists led to the development of a novel series of γ-butyrolactone derivatives. We were interested in understanding the contributions of the structural features of these molecules for receptor affinity and subtype selectivity, if any, to guide further design of second-generation analogs with tailor-made potency and selectivity. Initially, 3D pharmacophore hypotheses were developed using high affinity M1 and M2 antagonist ligands. The ‘extended’ and ‘compact’ hypotheses were then used for the retrospective virtual screening of the γ-butyrolactone derivatives. Further, these molecules were then docked into the M2 receptor orthosteric binding site. The results obtained from the pharmacophore- and structure-based investigations were in agreement with the structure–activity relationship (SAR) observations. The key findings of these studies will be helpful for further design and development of subtype-selective muscarinic receptor ligands.