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Study · Not a test of the peptide alone · 2026

10 results

Variant-specific pharmacophoric shifts in glucagon-like peptide-1 receptor-orforglipron complexes revealed by Boltz-2 co-folding and membrane molecular dynamics.

Mohammad A, Dashti M, Malik MDZ, Rajan R, Al-Mulla F

International journal of biological macromolecules13 Jul 2026

PMID42437645 (opens in a new tab)DOI10.1016/j.ijbiomac.2026.153525 (opens in a new tab)PepBankPUB-42437645
Publisher pagePubMedAsk about this study
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Summary

The text of this summary is not shown here, because the article license does not allow reuse. Read it at the source (opens in a new tab)

Text rights: CC BY-NC-ND. Results still quote short attributed sentences.

Results from this study10

No result from this study comes from a test of the peptide.

Studies that did not test the peptide alone10

In this study, Orforglipron was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking Orforglipron.

  1. 01Computer modelNot a test of Orforglipron aloneIn silicoMechanism

    In computational GLP-1R-orforglipron models, all variants enhanced MM/GBSA binding by 24-35% versus WT.

    In plain wordsComputer models predicted stronger orforglipron binding for all receptor variants than for the wild-type receptor.

    Peptide
    Orforglipron
    Outcome
    IncreaseMM/GBSA binding across variants
    Study

    n: not reported in source

    GLP-1R-orforglipron complexes
    Comparator
    Wild-type GLP-1R
    Outcome group
    Receptor activity and mechanism · Pharmacology

    Measurements

    Binding enhancement
    24 to 35%
    versus WT

    Source sentences

    Summary
    All variants exhibited enhanced MM/GBSA binding (24-35% vs WT) despite conformational destabilization, as evidenced by elevated RMSD, altered free energy landscapes, and reorganized H-bond networks.
    2 context sentences
    Summary · context
    We employed an integrative computational framework that combines Boltz-2 deep learning co-folding for variant complex generation, 500 ns all-atom molecular dynamics simulations in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid bilayer, MM/GBSA binding free-energy decomposition, and…
    Summary · context
    Wild-type (WT) GLP-1R and four clinically annotated variants L260F3.53b (TM3), G168S (stalk), R131Q (ECD), and A316T5.46 (TM5) were characterized.

    In this study, Orforglipron was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Orforglipron.

  2. 02Computer modelNot a test of Orforglipron aloneIn silicoMechanism

    In computational GLP-1R-orforglipron models, variants showed conformational destabilization versus WT, with elevated RMSD, altered energy landscapes, and reorganized hydrogen bonds.

    In plain wordsComputer models predicted less stable orforglipron-receptor conformations for variants than for the wild-type receptor.

    Peptide
    Orforglipron
    Outcome
    DecreaseConformational stability across variants
    Study

    n: not reported in source

    GLP-1R-orforglipron complexes
    Comparator
    Wild-type GLP-1R
    Outcome group
    Receptor activity and mechanism · Pharmacology

    Source sentences

    Summary
    All variants exhibited enhanced MM/GBSA binding (24-35% vs WT) despite conformational destabilization, as evidenced by elevated RMSD, altered free energy landscapes, and reorganized H-bond networks.
    2 context sentences
    Summary · context
    We employed an integrative computational framework that combines Boltz-2 deep learning co-folding for variant complex generation, 500 ns all-atom molecular dynamics simulations in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid bilayer, MM/GBSA binding free-energy decomposition, and…
    Summary · context
    Wild-type (WT) GLP-1R and four clinically annotated variants L260F3.53b (TM3), G168S (stalk), R131Q (ECD), and A316T5.46 (TM5) were characterized.

    In this study, Orforglipron was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Orforglipron.

  3. 03Computer modelNot a test of Orforglipron aloneIn silicoMechanism

    In computational WT GLP-1R-orforglipron models, Lys197 was the canonical anchor with 79.8% hydrogen-bond occupancy.

    In plain wordsComputer models identified Lys197 as the main binding anchor for orforglipron in the wild-type receptor.

    Peptide
    Orforglipron
    Outcome
    Not applicableLys197 hydrogen-bond occupancy in WT
    Study

    n: not reported in source

    GLP-1R-orforglipron complexes
    Outcome group
    Receptor activity and mechanism · Pharmacology

    Measurements

    Hydrogen-bond occupancy
    79.8%
    WT Lys197

    Source sentences

    Summary
    H-bond occupancy trajectory analysis identified Lys1972.67 as the canonical pharmacophoric anchor in WT (79.8%), preserved in L260F (57.1%) and A316T (63.9%).
    2 context sentences
    Summary · context
    We employed an integrative computational framework that combines Boltz-2 deep learning co-folding for variant complex generation, 500 ns all-atom molecular dynamics simulations in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid bilayer, MM/GBSA binding free-energy decomposition, and…
    Summary · context
    Wild-type (WT) GLP-1R and four clinically annotated variants L260F3.53b (TM3), G168S (stalk), R131Q (ECD), and A316T5.46 (TM5) were characterized.

    In this study, Orforglipron was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Orforglipron.

  4. 04Computer modelNot a test of Orforglipron aloneIn silicoMechanism

    In computational GLP-1R-orforglipron models, L260F preserved the Lys197 anchor with 57.1% occupancy versus 79.8% in WT.

    In plain wordsComputer models predicted that L260F preserved orforglipron's Lys197 anchor with lower occupancy than the wild-type receptor.

    Peptide
    Orforglipron
    Outcome
    DecreaseLys197 hydrogen-bond occupancy in L260F
    Study

    n: not reported in source

    GLP-1R-orforglipron complexes
    Comparator
    Wild-type GLP-1R
    Outcome group
    Receptor activity and mechanism · Pharmacology

    Source sentences

    Summary
    H-bond occupancy trajectory analysis identified Lys1972.67 as the canonical pharmacophoric anchor in WT (79.8%), preserved in L260F (57.1%) and A316T (63.9%).
    2 context sentences
    Summary · context
    We employed an integrative computational framework that combines Boltz-2 deep learning co-folding for variant complex generation, 500 ns all-atom molecular dynamics simulations in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid bilayer, MM/GBSA binding free-energy decomposition, and…
    Summary · context
    Wild-type (WT) GLP-1R and four clinically annotated variants L260F3.53b (TM3), G168S (stalk), R131Q (ECD), and A316T5.46 (TM5) were characterized.

    In this study, Orforglipron was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Orforglipron.

  5. 05Computer modelNot a test of Orforglipron aloneIn silicoMechanism

    In computational GLP-1R-orforglipron models, A316T preserved the Lys197 anchor with 63.9% occupancy versus 79.8% in WT.

    In plain wordsComputer models predicted that A316T preserved orforglipron's Lys197 anchor with lower occupancy than the wild-type receptor.

    Peptide
    Orforglipron
    Outcome
    DecreaseLys197 hydrogen-bond occupancy in A316T
    Study

    n: not reported in source

    GLP-1R-orforglipron complexes
    Comparator
    Wild-type GLP-1R
    Outcome group
    Receptor activity and mechanism · Pharmacology

    Source sentences

    Summary
    H-bond occupancy trajectory analysis identified Lys1972.67 as the canonical pharmacophoric anchor in WT (79.8%), preserved in L260F (57.1%) and A316T (63.9%).
    2 context sentences
    Summary · context
    We employed an integrative computational framework that combines Boltz-2 deep learning co-folding for variant complex generation, 500 ns all-atom molecular dynamics simulations in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid bilayer, MM/GBSA binding free-energy decomposition, and…
    Summary · context
    Wild-type (WT) GLP-1R and four clinically annotated variants L260F3.53b (TM3), G168S (stalk), R131Q (ECD), and A316T5.46 (TM5) were characterized.

    In this study, Orforglipron was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Orforglipron.

  6. 06Computer modelNot a test of Orforglipron aloneIn silicoMechanism

    In computational GLP-1R-orforglipron models, G168S lacked the Lys197 anchor and substituted Tyr205/Gln221.

    In plain wordsComputer models predicted that G168S used different orforglipron binding anchors than the wild-type receptor.

    Peptide
    Orforglipron
    Outcome
    Not applicableAnchor substitution in G168S
    Study

    n: not reported in source

    GLP-1R-orforglipron complexes
    Comparator
    Wild-type GLP-1R
    Outcome group
    Receptor activity and mechanism · Pharmacology

    Source sentences

    Summary
    However, Lys1972.67 was absent in G168S and R131Q, which substitute Tyr2052.75/Gln221 and Tyr202, respectively.
    2 context sentences
    Summary · context
    We employed an integrative computational framework that combines Boltz-2 deep learning co-folding for variant complex generation, 500 ns all-atom molecular dynamics simulations in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid bilayer, MM/GBSA binding free-energy decomposition, and…
    Summary · context
    Wild-type (WT) GLP-1R and four clinically annotated variants L260F3.53b (TM3), G168S (stalk), R131Q (ECD), and A316T5.46 (TM5) were characterized.

    In this study, Orforglipron was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Orforglipron.

  7. 07Computer modelNot a test of Orforglipron aloneIn silicoMechanism

    In computational GLP-1R-orforglipron models, R131Q lacked the Lys197 anchor and substituted Tyr202.

    In plain wordsComputer models predicted that R131Q used a different orforglipron binding anchor than the wild-type receptor.

    Peptide
    Orforglipron
    Outcome
    Not applicableAnchor substitution in R131Q
    Study

    n: not reported in source

    GLP-1R-orforglipron complexes
    Comparator
    Wild-type GLP-1R
    Outcome group
    Receptor activity and mechanism · Pharmacology

    Source sentences

    Summary
    However, Lys1972.67 was absent in G168S and R131Q, which substitute Tyr2052.75/Gln221 and Tyr202, respectively.
    2 context sentences
    Summary · context
    We employed an integrative computational framework that combines Boltz-2 deep learning co-folding for variant complex generation, 500 ns all-atom molecular dynamics simulations in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid bilayer, MM/GBSA binding free-energy decomposition, and…
    Summary · context
    Wild-type (WT) GLP-1R and four clinically annotated variants L260F3.53b (TM3), G168S (stalk), R131Q (ECD), and A316T5.46 (TM5) were characterized.

    In this study, Orforglipron was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Orforglipron.

  8. 08Computer modelNot a test of Orforglipron aloneIn silicoMechanism

    In computational GLP-1R-orforglipron models, G168S had the strongest binding at -117.18 kcal/mol through compensatory contacts.

    In plain wordsComputer models predicted the strongest orforglipron binding for G168S compared with the other receptor models.

    Peptide
    Orforglipron
    Outcome
    IncreaseG168S binding energy
    Study

    n: not reported in source

    GLP-1R-orforglipron complexes
    Comparator
    Other receptor models
    Outcome group
    Receptor activity and mechanism · Pharmacology

    Measurements

    Binding energy
    −117.18 kcal/mol
    G168S

    Source sentences

    Summary
    G168S exhibited the strongest binding (-117.18 kcal/mol) through compensatory contacts, while displaying a diffuse free-energy landscape and conformational disorder.
    2 context sentences
    Summary · context
    We employed an integrative computational framework that combines Boltz-2 deep learning co-folding for variant complex generation, 500 ns all-atom molecular dynamics simulations in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid bilayer, MM/GBSA binding free-energy decomposition, and…
    Summary · context
    Wild-type (WT) GLP-1R and four clinically annotated variants L260F3.53b (TM3), G168S (stalk), R131Q (ECD), and A316T5.46 (TM5) were characterized.

    In this study, Orforglipron was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Orforglipron.

  9. 09Computer modelNot a test of Orforglipron aloneIn silicoMechanism

    In computational GLP-1R-orforglipron models, G168S displayed a diffuse free-energy landscape and conformational disorder.

    In plain wordsComputer models predicted diffuse energy states and conformational disorder in the G168S-orforglipron complex.

    Peptide
    Orforglipron
    Outcome
    Not applicableG168S conformational dynamics
    Study

    n: not reported in source

    GLP-1R-orforglipron complexes
    Outcome group
    Receptor activity and mechanism · Pharmacology

    Source sentences

    Summary
    G168S exhibited the strongest binding (-117.18 kcal/mol) through compensatory contacts, while displaying a diffuse free-energy landscape and conformational disorder.
    2 context sentences
    Summary · context
    We employed an integrative computational framework that combines Boltz-2 deep learning co-folding for variant complex generation, 500 ns all-atom molecular dynamics simulations in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid bilayer, MM/GBSA binding free-energy decomposition, and…
    Summary · context
    Wild-type (WT) GLP-1R and four clinically annotated variants L260F3.53b (TM3), G168S (stalk), R131Q (ECD), and A316T5.46 (TM5) were characterized.

    In this study, Orforglipron was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Orforglipron.

  10. 10Computer modelNot a test of Orforglipron aloneIn silicoMechanism

    In computational GLP-1R-orforglipron models, A316T showed bistable dynamics related to Y242-T316 hydrogen-bond-mediated constitutive activation while preserving canonical engagement.

    In plain wordsComputer models predicted two dynamic states in the A316T-orforglipron complex, while its usual binding engagement remained.

    Peptide
    Orforglipron
    Outcome
    Not applicableA316T bistable dynamics
    Study

    n: not reported in source

    GLP-1R-orforglipron complexes
    Outcome group
    Receptor activity and mechanism · Pharmacology

    Source sentences

    Summary
    A316T exhibited bistable dynamics related to Y2423.45-T3165.46H-bond-mediated constitutive activation, while preserving canonical engagement.
    2 context sentences
    Summary · context
    We employed an integrative computational framework that combines Boltz-2 deep learning co-folding for variant complex generation, 500 ns all-atom molecular dynamics simulations in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid bilayer, MM/GBSA binding free-energy decomposition, and…
    Summary · context
    Wild-type (WT) GLP-1R and four clinically annotated variants L260F3.53b (TM3), G168S (stalk), R131Q (ECD), and A316T5.46 (TM5) were characterized.

    In this study, Orforglipron was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Orforglipron.

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

  1. Version 2Current

    14 Oct 2026, 05:02 UTC

    Study results updated

  2. Version 1

    14 Oct 2026, 01:46 UTC

    First added · source update from Europe PMC

Subjects

Terms as the source lists them.

Publication types

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