Abstract
Drugs that treat chronic obstructive pulmonary disease by antagonizing the M3 muscarinic acetylcholine receptor (M3R) have had a significant effect on health, but can suffer from their lack of selectivity against the M2R subtype, which modulates heart rate. Beginning with the crystal structures of M2R and M3R, we exploited a single amino acid difference in their orthosteric binding pockets using molecular docking and structure-based design. The resulting M3R antagonists had up to 100-fold selectivity over M2R in affinity and over 1,000-fold selectivity in vivo. The crystal structure of the M3R-selective antagonist in complex with M3R corresponded closely to the docking-predicted geometry, providing a template for further optimization.
Highlights
Drugs that treat chronic obstructive pulmonary disease by antagonizing the M3 muscarinic acetylcholine receptor (M3R) have had a significant effect on health, but can suffer from their lack of selectivity against the M2R subtype, which modulates heart rate
We began with the nonselective antagonists 3-quinuclidinylbenzilate (QNB) [14] and tiotropium [15], related molecules that adopt similar binding modes in the X-ray structures of M2R and M3R, respectively [8, 9] (Fig. 1 A and B)
Docking studies suggested that the tolerance of both muscarinic subtypes toward enlargement of the upward-directed B substituent of QNB or tiotropium may be explained by flexibility of the link between the two arene moieties, allowing the upwardfacing ring to avoid a clash with Phe181
Summary
Drugs that treat chronic obstructive pulmonary disease by antagonizing the M3 muscarinic acetylcholine receptor (M3R) have had a significant effect on health, but can suffer from their lack of selectivity against the M2R subtype, which modulates heart rate. | | | muscarinic receptor G protein-coupled receptor drug design | subtype selectivity crystal structure Docking studies suggested that the tolerance of both muscarinic subtypes toward enlargement of the upward-directed B substituent of QNB or tiotropium may be explained by flexibility of the link between the two arene moieties, allowing the upwardfacing ring to avoid a clash with Phe181
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