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Prediction of consensus binding mode geometries for related chemical series of positive allosteric modulators of adenosine and muscarinic acetylcholine receptors.

ABSTRACT: Following insights from recent crystal structures of the muscarinic acetylcholine receptor, binding modes of Positive Allosteric Modulators (PAMs) were predicted under the assumption that PAMs should bind to the extracellular surface of the active state. A series of well-characterized PAMs for adenosine (A1 R, A2A R, A3 R) and muscarinic acetylcholine (M1 R, M5 R) receptors were modeled using both rigid and flexible receptor CHARMM-based molecular docking. Studies of adenosine receptors investigated the molecular basis of the probe-dependence of PAM activity by modeling in complex with specific agonist radioligands. Consensus binding modes map common pharmacophore features of several chemical series to specific binding interactions. These models provide a rationalization of how PAM binding slows agonist radioligand dissociation kinetics. M1 R PAMs were predicted to bind in the analogous M2 R PAM LY2119620 binding site. The M5 R NAM (ML-375) was predicted to bind in the PAM (ML-380) binding site with a unique induced-fit receptor conformation. © 2017 Wiley Periodicals, Inc.

SUBMITTER: Sakkal LA

PROVIDER: S-EPMC5403616 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Prediction of consensus binding mode geometries for related chemical series of positive allosteric modulators of adenosine and muscarinic acetylcholine receptors.

Sakkal Leon A LA Rajkowski Kyle Z KZ Armen Roger S RS

Journal of computational chemistry 20170128 15

Following insights from recent crystal structures of the muscarinic acetylcholine receptor, binding modes of Positive Allosteric Modulators (PAMs) were predicted under the assumption that PAMs should bind to the extracellular surface of the active state. A series of well-characterized PAMs for adenosine (A1 R, A2A R, A3 R) and muscarinic acetylcholine (M1 R, M5 R) receptors were modeled using both rigid and flexible receptor CHARMM-based mol ...[more]

PMID: 28130813

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Project description:Acetylcholine activates nicotinic acetylcholine receptors (nAChRs) by binding to an extracellular site located at the interface of two adjacent subunits. In contrast, recent studies have provided evidence that positive allosteric modulators (PAMs) such as TQS (4-(naphthalen-2-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide) and allosteric agonists such as 4BP-TQS (4-(4-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide) interact at an intrasubunit transmembrane site. Here, we describe the synthesis and pharmacological characterization of a series of chemically related allosteric modulators of the α7 nAChR. Minimal changes in the chemical structure of these compounds have been found to exert profound effects on their pharmacological properties. For example, compounds containing a bromine atom at either the ortho or meta position on the phenyl ring, such as 2BP-TQS (4-(2-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide) and 3BP-TQS (4-(3-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide), rather than at the para position (4BP-TQS), display no allosteric agonist activity but retain PAM activity on α7 nAChRs, demonstrating the importance of the location of the halogen atom on pharmacological properties. Replacement of the bromine atom in 4BP-TQS with either a chlorine [4CP-TQS (4-(4-chloroophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide)] or an iodine atom [4IP-TQS (4-(4-iodoophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide)] results in compounds that have pharmacological properties characteristic of allosteric agonists but display differences in activation rates, in inactivation rates, and in levels of desensitization. In contrast, replacement of the bromine atom in 4BP-TQS with a fluorine atom [4FP-TQS (4-(4-fluorophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide)] generated a compound that lacks allosteric agonist activity but acts a potentiator of responses to acetylcholine. In addition, 4FP-TQS was found to act as an antagonist of responses evoked by allosteric agonists such as 4BP-TQS. These findings provide evidence of the pharmacological diversity of compounds interacting with the allosteric transmembrane site on α7 nAChRs.

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Prediction of consensus binding mode geometries for related chemical series of positive allosteric modulators of adenosine and muscarinic acetylcholine receptors.

Publications

Prediction of consensus binding mode geometries for related chemical series of positive allosteric modulators of adenosine and muscarinic acetylcholine receptors.

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