Sourcing the affinity of flavonoids for the glycogen phosphorylase inhibitor site via crystallography, kinetics and QM/MM-PBSA binding studies: Comparison of chrysin and flavopiridol

Tsitsanou, Katerina E.; Hayes, Joseph M.; Keramioti, Maria; Mamais, Michael; Oikonomakos, Nikos G.; Kato, Atsushi; Leonidas, D.D.; Zographos, S.E.

doi:10.1016/j.fct.2012.12.030

Cited by 32 publications

(58 citation statements)

References 72 publications

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“…Although docking failed to correctly rank inhibitor binding conformations, the QM/MM-PBSA method was superior to model the hydrophobic (stacking) interactions correctly and reproduce experimental results [14]. Favopiridols' greater binding affinity may be a result of favorable interactions of the cationic 4-hydroxypiperidin-1-yl substituent with GPb, with desolvation effects limited by the substituent conformation adopted in the crystallographic complex [14]. Successful predictions were repeated using QM/MM-PBSA for the flavonoid quercetagetin (which binds at the allosteric site), and the data strongly suggests this computational methodology as an economic and accurate tool to predict flavonoid binding [14].…”

Section: Overview Of Flavonoid/protein Complexes Relevant For Drug Dementioning

confidence: 97%

“…α-Amylase cleaves starch to liberate glucose so inhibition of this enzyme potentially drops glucose levels in the blood. The inhibition of glycogen phosphorylase makes this enzyme a target for drugs for Type II Diabetes (PDB code 3EBP) [14]. Flavonoids have been discovered to inhibit glycogen phosphorylase (GP), a target to control hyperglycemia in type 2 diabetes.…”

Section: Overview Of Flavonoid/protein Complexes Relevant For Drug Dementioning

confidence: 99%

“…Chrysin binds to GPb approximately 15 times weaker (Ki=19.01 µM) than flavopiridol (Ki=1.24 µM), exclusively at the inhibitor site, and both inhibitors display similar behavior with respect to AMP. To identify the source of flavopiridols' stronger affinity, molecular docking with Glide and post docking binding free energy calculations using QM/MM-PBSA were performed and compared" [14]. Although docking failed to correctly rank inhibitor binding conformations, the QM/MM-PBSA method was superior to model the hydrophobic (stacking) interactions correctly and reproduce experimental results [14].…”

Section: Overview Of Flavonoid/protein Complexes Relevant For Drug Dementioning

confidence: 99%

“…To identify the source of flavopiridols' stronger affinity, molecular docking with Glide and post docking binding free energy calculations using QM/MM-PBSA were performed and compared" [14]. Although docking failed to correctly rank inhibitor binding conformations, the QM/MM-PBSA method was superior to model the hydrophobic (stacking) interactions correctly and reproduce experimental results [14]. Favopiridols' greater binding affinity may be a result of favorable interactions of the cationic 4-hydroxypiperidin-1-yl substituent with GPb, with desolvation effects limited by the substituent conformation adopted in the crystallographic complex [14].…”

Section: Overview Of Flavonoid/protein Complexes Relevant For Drug Dementioning

confidence: 99%

“…Favopiridols' greater binding affinity may be a result of favorable interactions of the cationic 4-hydroxypiperidin-1-yl substituent with GPb, with desolvation effects limited by the substituent conformation adopted in the crystallographic complex [14]. Successful predictions were repeated using QM/MM-PBSA for the flavonoid quercetagetin (which binds at the allosteric site), and the data strongly suggests this computational methodology as an economic and accurate tool to predict flavonoid binding [14]. As shown in Figure 2, the human pancreatic alpha-amylase in complex with myricetin (MYC) PDB code 4GQR shows a hydrophobic pocket flanked by try59 and Tyr62 ( Figure 2).…”

Section: Overview Of Flavonoid/protein Complexes Relevant For Drug Dementioning

confidence: 99%

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Structural Analysis of Flavonoid/Drug Target Complexes: Natural Products as Lead Compounds for Drug Development

Sosa¹,

Sosa²,

Phansalkar³

et al. 2017

Nat Prod Chem Res

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Plants produce pigments called flavonoids that are synthesized (de novo) primarily from the amino acid phenylalanine. Many natural products such as herb preparations for medicinal use contain flavonoids and so these diverse structural compounds have become potential lead compounds for a variety of illnesses ranging from specific cancers to gout. Recently, Biotechnology has been utilized through bioorganic engineering to manufacture flavonoid and modified flavonoids for medicinal applications. A growing number of protein-flavonoid complexes have been crystallized and their structures solved in the last decade. A summary of the protein-flavonoid complexes with medicinal relevance is presented herein. A detailed analysis of selected protein-flavonoid complexes is provided. The goal is to provide insights for modifications to known flavonoids that could be biomanufactured to generate more specific and efficient binding of flavonoids to protein targets with medicinal relevance.

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Section: Overview Of Flavonoid/protein Complexes Relevant For Drug Dementioning

confidence: 97%

Section: Overview Of Flavonoid/protein Complexes Relevant For Drug Dementioning

confidence: 99%

Section: Overview Of Flavonoid/protein Complexes Relevant For Drug Dementioning

confidence: 99%

Section: Overview Of Flavonoid/protein Complexes Relevant For Drug Dementioning

confidence: 99%

Section: Overview Of Flavonoid/protein Complexes Relevant For Drug Dementioning

confidence: 99%

See 3 more Smart Citations

Structural Analysis of Flavonoid/Drug Target Complexes: Natural Products as Lead Compounds for Drug Development

Sosa¹,

Sosa²,

Phansalkar³

et al. 2017

Nat Prod Chem Res

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SAMPL7 TrimerTrip host–guest binding affinities from extensive alchemical and end-point free energy calculations

Huai

Yang

et al. 2020

J Comput Aided Mol Des

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The prediction of host-guest binding affinities with computational modelling is still a challenging task.In the 7 th statistical assessment of the modeling of proteins and ligands (SAMPL) challenge, a new host named TrimerTrip was synthesized and the thermodynamic parameters of 16 structurally diverse guests binding to the host were characterized. In the TrimerTrip-guest challenge, only structures of the host and the guests are provided, which indicates that the predictions of both the binding poses and the binding affinities are under assessment. In this work, starting from the binding poses obtained from our previous enhanced sampling simulations in the configurational space, we perform extensive alchemical and end-point free energy calculations to calculate the host-guest binding affinities retrospectively. The alchemical predictions with two widely accepted charge schemes (i.e. AM1-BCC and RESP) are in good agreement with the experimental reference, while the end-point estimates perform poorly in reproducing the experimental binding affinities. Aside from the absolute value of the binding affinity, the rank of binding free energies is also crucial in drug design. Surprisingly, the end-point MM/PBSA method seems very powerful in reproducing the experimental rank of binding affinities. Although the length of our simulations is long and the intermediate spacing is dense, the convergence behavior is not very good, which may arise from the flexibility of the host molecule. Enhanced sampling techniques in the configurational space may be required to obtain fully converged sampling. Further, as the length of sampling in alchemical free energy calculations already achieves several hundred ns, performing direct simulations of the binding/unbinding event in the 2 / 27 physical space could be more useful and insightful. More details about the binding pathway and mechanism could be obtained in this way. The nonequilibrium method could also be a nice choice if one insists to use the alchemical method, as the intermediate sampling is avoided to some extent.

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Binding thermodynamics and interaction patterns of human purine nucleoside phosphorylase-inhibitor complexes from extensive free energy calculations

Huai

Yang

Sun

2021

J Comput Aided Mol Des

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Sourcing the affinity of flavonoids for the glycogen phosphorylase inhibitor site via crystallography, kinetics and QM/MM-PBSA binding studies: Comparison of chrysin and flavopiridol

Cited by 32 publications

References 72 publications

Structural Analysis of Flavonoid/Drug Target Complexes: Natural Products as Lead Compounds for Drug Development

Structural Analysis of Flavonoid/Drug Target Complexes: Natural Products as Lead Compounds for Drug Development

SAMPL7 TrimerTrip host–guest binding affinities from extensive alchemical and end-point free energy calculations

Binding thermodynamics and interaction patterns of human purine nucleoside phosphorylase-inhibitor complexes from extensive free energy calculations

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