Identifying Potential Ligand Binding Sites on Glycogen Synthase Kinase 3 Using Atomistic Cosolvent Simulations

DasGupta, Debarati; Mehrani, Ramin; Carlson, Heather A.; Sharma, Sumit

doi:10.1021/acsabm.2c01079

Cited by 2 publications

(1 citation statement)

References 47 publications

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“…Interestingly, COB-136 has strong affinity for an off-target binding site on GSK-3β located in the β-sheet region close to the N-terminus rather than for the ATP or the substrate binding site. The ATP-binding, substrate-binding, and S3-binding sites found in the MSM were also identified previously using the mixed solvent MD approach . MSM estimates the transition rates or flux between the different macrostates.…”

Section: Resultsmentioning

confidence: 92%

Capturing the Effects of Single Atom Substitutions on the Inhibition Efficiency of Glycogen Synthase Kinase-3β Inhibitors via Markov State Modeling and Experiments

Mehrani,

Mondal,

Ghazanfari

et al. 2024

J. Chem. Theory Comput.

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Small modifications in the chemical structure of ligands are known to dramatically change their ability to inhibit the activity of a protein. Unraveling the mechanisms that govern these dramatic changes requires scrutinizing the dynamics of protein−ligand binding and unbinding at the atomic level. As an exemplary case, we have studied Glycogen Synthase Kinase-3β (GSK-3β), a multifunctional kinase that has been implicated in a host of pathological processes. As such, there is a keen interest in identifying ligands that inhibit GSK-3β activity. One family of compounds that are highly selective and potent inhibitors of GSK-3β is exemplified by a molecule termed COB-187. COB-187 consists of a five-member heterocyclic ring with a thione at C 2 , a pyridine substituted methyl at N 3 , and a hydroxyl and phenyl at C 4 . We have studied the inhibition of GSK-3β by COB-187related ligands that differ in a single heavy atom from each other (either in the location of nitrogen in their pyridine ring, or with the pyridine ring replaced by a phenyl ring), or in the length of the alkyl group joining the pyridine and the N 3 . The inhibition experiments show a large range of half-maximal inhibitory concentration (IC 50 ) values from 10 nM to 10 μM, implying that these ligands exhibit vastly different propensities to inhibit GSK-3β. To explain these differences, we perform Markov State Modeling (MSM) using fully atomistic simulations. Our MSM results are in excellent agreement with the experiments in that they accurately capture differences in the binding propensities of the ligands. The simulations show that the binding propensities are related to the ligands' ability to attain a compact conformation where their two aromatic rings are spatially close. We rationalize this result by sampling numerous binding and unbinding events via funnel metadynamics simulations, which show that indeed while approaching the bound state, the ligands prefer to be in their compact conformation. We find that the presence of nitrogen in the aromatic ring increases the probability of attaining the compact conformation. Protein−ligand binding is understood to be dictated by the energetics of interactions and entropic factors, like the release of bound water from the binding pockets. This work shows that changes in the conformational distribution of ligands due to atom-level modifications in the structure play an important role in protein−ligand binding.

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Section: Resultsmentioning

confidence: 92%

Capturing the Effects of Single Atom Substitutions on the Inhibition Efficiency of Glycogen Synthase Kinase-3β Inhibitors via Markov State Modeling and Experiments

Mehrani,

Mondal,

Ghazanfari

et al. 2024

J. Chem. Theory Comput.

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Toward Unveiling Putative Binding Sites of Interleukin-33: Insights from Mixed-Solvent Molecular Dynamics Simulations of the Interleukin-1 Family

Mai,

Lam,

Pham

et al. 2024

J. Phys. Chem. B

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The interleukin (IL)-1 family is a major proinflammatory cytokine family, ranging from the well-studied IL-1s to the most recently discovered IL-33. As a new focus, IL-33 has attracted extensive research for its crucial immunoregulatory roles, leading to the development of notable monoclonal antibodies as clinical candidates. Efforts to develop small molecules disrupting IL-33/ST2 interaction remain highly desired but encounter challenges due to the shallow and featureless interfaces. The information from relative cytokines has shown that traditional binding site identification methods still struggle in mapping cryptic sites, necessitating dynamic approaches to uncover druggable pockets on IL-33. Here, we employed mixed-solvent molecular dynamics (MixMD) simulations with diverse-property probes to map the hotspots of IL-33 and identify potential binding sites. The protocol was first validated using the known binding sites of two IL-1 family members and then applied to the structure of IL-33. Our simulations revealed several binding sites and proposed sidechain rearrangements essential for the binding of a known inhibitor, aligning well with experimental NMR findings. Further microsecond-time scale simulations of this IL-33-protein complex unveiled distinct binding modes with varying occurrences. These results could facilitate future efforts in developing ligands to target challenging flexible pockets of IL-33 and IL-1 family cytokines in general.

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Identifying Potential Ligand Binding Sites on Glycogen Synthase Kinase 3 Using Atomistic Cosolvent Simulations

Cited by 2 publications

References 47 publications

Capturing the Effects of Single Atom Substitutions on the Inhibition Efficiency of Glycogen Synthase Kinase-3β Inhibitors via Markov State Modeling and Experiments

Capturing the Effects of Single Atom Substitutions on the Inhibition Efficiency of Glycogen Synthase Kinase-3β Inhibitors via Markov State Modeling and Experiments

Toward Unveiling Putative Binding Sites of Interleukin-33: Insights from Mixed-Solvent Molecular Dynamics Simulations of the Interleukin-1 Family

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