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

Sakkal, Leon A.; Rajkowski, Kyle Z.; Armen, Roger S.

doi:10.1002/jcc.24728

Cited by 6 publications

(6 citation statements)

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“…In a previously published assessment of docking accuracy, these CHARMM-based docking methods were shown to have the highest “discriminative power”to correctly predict binding geometries over diverse classes of protein-ligand interactions compared to other common scoring functions [ 83 , 84 ]. Molecular docking utilized the LPDB CHARMm force field [ 85 , 86 ], the Linear Interaction Energy (LIE) scoring approach to approximate the free energy of binding (ΔG bind ) has been previously described [ 84 , 87 ] and have also been specifically assessed for their use in calculating ligand efficiencies in computational medicinal chemistry applications [ 84 ]. For aromatic pharmacophore sites selected for being sufficiently favorable, computational fragment screening was performed using identified benzene coordinates as X,Y,Z center of mass reference positions.…”

Section: Methodsmentioning

confidence: 99%

Mapping major SARS-CoV-2 drug targets and assessment of druggability using computational fragment screening: Identification of an allosteric small-molecule binding site on the Nsp13 helicase

Freidel

Armen

2021

PLoS ONE

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The 2019 emergence of, SARS-CoV-2 has tragically taken an immense toll on human life and far reaching impacts on society. There is a need to identify effective antivirals with diverse mechanisms of action in order to accelerate preclinical development. This study focused on five of the most established drug target proteins for direct acting small molecule antivirals: Nsp5 Main Protease, Nsp12 RNA-dependent RNA polymerase, Nsp13 Helicase, Nsp16 2’-O methyltransferase and the S2 subunit of the Spike protein. A workflow of solvent mapping and free energy calculations was used to identify and characterize favorable small-molecule binding sites for an aromatic pharmacophore (benzene). After identifying the most favorable sites, calculated ligand efficiencies were compared utilizing computational fragment screening. The most favorable sites overall were located on Nsp12 and Nsp16, whereas the most favorable sites for Nsp13 and S2 Spike had comparatively lower ligand efficiencies relative to Nsp12 and Nsp16. Utilizing fragment screening on numerous possible sites on Nsp13 helicase, we identified a favorable allosteric site on the N-terminal zinc binding domain (ZBD) that may be amenable to virtual or biophysical fragment screening efforts. Recent structural studies of the Nsp12:Nsp13 replication-transcription complex experimentally corroborates ligand binding at this site, which is revealed to be a functional Nsp8:Nsp13 protein-protein interaction site in the complex. Detailed structural analysis of Nsp13 ZBD conformations show the role of induced-fit flexibility in this ligand binding site and identify which conformational states are associated with efficient ligand binding. We hope that this map of over 200 possible small-molecule binding sites for these drug targets may be of use for ongoing discovery, design, and drug repurposing efforts. This information may be used to prioritize screening efforts or aid in the process of deciphering how a screening hit may bind to a specific target protein.

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Section: Methodsmentioning

confidence: 99%

Mapping major SARS-CoV-2 drug targets and assessment of druggability using computational fragment screening: Identification of an allosteric small-molecule binding site on the Nsp13 helicase

Freidel

Armen

2021

PLoS ONE

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“…Structural modeling was performed with our established methods (48). Figures were prepared based on structures of myristoylated PKAc (PDB code 4DFX) (14).…”

Section: Modeling Structurementioning

confidence: 99%

A tripartite cooperative mechanism confers resistance of the protein kinase A catalytic subunit to dephosphorylation

Chan

Armen

Yadav

et al. 2020

Journal of Biological Chemistry

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Phosphorylation of specific residues in the activation loops of AGC kinase group (protein kinase A, G, and C families) is required for activity of most of these kinases, including the catalytic subunit of PKA (PKAc). Although many phosphorylated AGC kinases are sensitive to phosphatase-mediated dephosphorylation, the PKAc activation loop uniquely resists dephosphorylation, rendering it “constitutively” phosphorylated in cells. Previous biophysical experiments and structural modeling have suggested that the N-terminal myristoylation signal and the C-terminal FXXF motif in PKAc regulate its thermal stability and catalysis. Here, using site-directed mutagenesis, molecular modeling, and in cell-free and cell-based systems, we demonstrate that substitutions of either the PKAc myristoylation signal or the FXXF motif only modestly reduce phosphorylation and fail to affect PKAc function in cells. However, we observed that these two sites cooperate with an N-terminal FXXW motif to cooperatively establish phosphatase resistance of PKAc while not affecting kinase-dependent phosphorylation of the activation loop. We noted that this tripartite cooperative mechanism of phosphatase resistance is functionally relevant, as demonstrated by changes in morphology, adhesion, and migration of human airway smooth muscle cells transfected with PKAc variants containing amino acid substitutions in these three sites. These findings establish that three allosteric sites located at the PKAc N and C termini coordinately regulate the phosphatase sensitivity of this enzyme. This cooperative mechanism of phosphatase resistance of AGC kinase opens new perspectives toward therapeutic manipulation of kinase signaling in disease.

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“…With the allosteric modulation of M 5 garnering interest, the Armen group conducted computational investigations into modes of binding for M 5 PAMs and NAMs ( 10 and 15 , respectively) . Homology models of human M 5 and human M 1 were constructed in a similar fashion to that utilized by Zheng et al Using the reported crystal structure of hM 2 simultaneously bound to the agonist iperoxo and the nonselective PAM LY2119620, it was shown that 10 occupies a binding site analogous to PAMs at human M 1 .…”

Section: Selective Modulation Of M5mentioning

confidence: 99%

The Muscarinic Acetylcholine Receptor M₅: Therapeutic Implications and Allosteric Modulation

Bender

Garrison

Lindsley

2018

ACS Chem. Neurosci.

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The muscarinic acetylcholine receptor (mAChR) subtype 5 (M5) was the most recent mAChR to be cloned and has since emerged as a potential therapeutic target for a number of indications. Early studies with knockout animals have provided clues to the receptor’s role in physiological processes related to Alzheimer’s disease, schizophrenia, and addiction, and until recently, useful subtype-selective tools to further probe the pharmacology of M5 have remained elusive. Small-molecule allosteric modulators have since gained traction as a means by which to selectively examine muscarinic pharmacology. This review highlights the discovery and optimization of M5 positive allosteric modulators (PAMs) and negative allosteric modulators (NAMs).

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

Cited by 6 publications

References 103 publications

Mapping major SARS-CoV-2 drug targets and assessment of druggability using computational fragment screening: Identification of an allosteric small-molecule binding site on the Nsp13 helicase

Mapping major SARS-CoV-2 drug targets and assessment of druggability using computational fragment screening: Identification of an allosteric small-molecule binding site on the Nsp13 helicase

A tripartite cooperative mechanism confers resistance of the protein kinase A catalytic subunit to dephosphorylation

The Muscarinic Acetylcholine Receptor M₅: Therapeutic Implications and Allosteric Modulation

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

Cited by 6 publications

References 103 publications

Mapping major SARS-CoV-2 drug targets and assessment of druggability using computational fragment screening: Identification of an allosteric small-molecule binding site on the Nsp13 helicase

Mapping major SARS-CoV-2 drug targets and assessment of druggability using computational fragment screening: Identification of an allosteric small-molecule binding site on the Nsp13 helicase

A tripartite cooperative mechanism confers resistance of the protein kinase A catalytic subunit to dephosphorylation

The Muscarinic Acetylcholine Receptor M5: Therapeutic Implications and Allosteric Modulation

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The Muscarinic Acetylcholine Receptor M₅: Therapeutic Implications and Allosteric Modulation