Regulation of protein-ligand binding affinity by hydrogen bond pairing

Chen, Deliang; Oezguen, Numan; Urvil, Petri; Ferguson, Colin G.; Dann, Sara M.; Savidge, Tor

doi:10.1126/sciadv.1501240

Cited by 601 publications

(388 citation statements)

References 54 publications

Supporting

Mentioning

371

Contrasting

Unclassified

Order By: Relevance

“…These experimental findings validate the model as fitting beyond its approximations. Chen et al [354] further validate Eq. 22 by showing that strong H-bonds in different pairing models have opposing effects on experimental binding free energy.…”

Section: The H-bond Pairing Principle Applied To Protein-ligand Intermentioning

confidence: 90%

“…Thus, the calculated ΔΔG is −25.8 ± 3.7 kJ/mol, which is in close agreement to the experimental ΔΔG (−25.6 kJ/mol at 298 K). On this basis, Chen et al [354] conclude that the s-s pairing H-bonds between the cyano group of 63 and the receptor tyrosine hydroxyls can markedly increase the binding affinity. Further evidence that shows that the H-bond interactions between the inhibitor 63 CN group and the receptor tyrosine hydroxyls are strong and favorable to binding affinity is based on their geometry and large effects on binding affinity.…”

Section: The H-bond Pairing Principle Applied To Protein-ligand Intermentioning

confidence: 99%

“…The ΔG for the H-bond competing process of two ligand atoms with the same protein atom(s) can be expressed as shown in Eq. 22 [354] ( ) ( )…”

Section: The H-bond Pairing Principle Applied To Protein-ligand Intermentioning

confidence: 99%

“…20 favors (both in enthalpy and in free energy) the pairing A 2 ···H-D 2 . Chen et al [354] estimated the H-bonding capability of an atom using the free energy required to transfer the atom from water to hexadecane. They then used a modification of the method of Kenny et al [355] to evaluate the Hbonding capability of the respective atoms in the proteinligand complex by calculating the difference (ΔlogP 16 ) between water/hexadecane partition coefficients (logP 16 ) and logP 16 of saturated hydrocarbon molecules with the same molecular surface area.…”

Section: Types Of Hydrogen Bondsmentioning

confidence: 99%

“…19 provides useful quantitative information in deciphering how protein-ligand H-bonds may modulate ligand binding affinity. To address the first issue of competing H-bonds in bulk water, Chen et al [354] proposed a new H-bond pairing principle to evaluate the ΔG in Eq. 19, and demonstrate that the nature of these H-bonds depends on the pairing of the donors and acceptors.…”

Section: Types Of Hydrogen Bondsmentioning

confidence: 99%

See 4 more Smart Citations

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

Yunta¹

2017

AJMO

View full text Add to dashboard Cite

The effect of weak intermolecular interactions on the binding affinity between ligand-protein complexes plays an important role in stabilizing a ligand at the interface of a protein structure. In this review article, we will explore the different ways of taking into account these interactions, mainly intramolecular hydrogen bonds, in docking calculations. Their possible limitations and their suitable application domains are highlighted. Inspection of the outliers of this study probed very stimulating, as it provides opportunities and inspiration to medicinal chemists, being a reminder of the impact that minimal chemical modifications can have on biological activities.

show abstract

Section: The H-bond Pairing Principle Applied To Protein-ligand Intermentioning

confidence: 90%

Section: The H-bond Pairing Principle Applied To Protein-ligand Intermentioning

confidence: 99%

“…The ΔG for the H-bond competing process of two ligand atoms with the same protein atom(s) can be expressed as shown in Eq. 22 [354] ( ) ( )…”

Section: The H-bond Pairing Principle Applied To Protein-ligand Intermentioning

confidence: 99%

Section: Types Of Hydrogen Bondsmentioning

confidence: 99%

Section: Types Of Hydrogen Bondsmentioning

confidence: 99%

See 3 more Smart Citations

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

Yunta¹

2017

AJMO

View full text Add to dashboard Cite

show abstract

Design, Synthesis, and Biological Evaluation of Novel Quercetin Derivatives as PPAR‐γ Partial Agonists by Modulating Epithelial–Mesenchymal Transition in Lung Cancer Metastasis

et al. 2023

View full text Add to dashboard Cite

Epithelial‐to‐mesenchymal transition (EMT) is responsible for driving metastasis of multiple cancer types including lung cancer. Peroxisome proliferator‐activated receptor (PPAR)‐γ, a ligand‐activated transcription factor, controls expression of variety of genes involved in EMT. Although several synthetic compounds act as potent full agonists for PPAR‐γ, their long term application is restricted due to serious adverse effects. Therefore, partial agonists involving reduced and balanced PPAR‐γ activity are more effective and valued. A previous study discerned the efficacy of quercetin and its derivatives to attain favorable stabilization with PPAR‐γ. Here this work is extended by synthesizing five novel quercetin derivatives (QDs) namely thiosemicarbazone (QUETSC)) and hydrazones (quercetin isonicotinic acid hydrazone (QUEINH), quercetin nicotinic acid hydrazone (QUENH), quercetin 2‐furoic hydrazone (QUE2FH), and quercetin salicyl hydrazone (QUESH)) and their effects are analyzed in modulating EMT in lung cancer cell lines via PPAR‐γ partial activation. QDs‐treated A549 cells diminish cell proliferation strongly at nanomolar concentration compared to NCI‐H460 cells. Of the five screened derivatives, QUETSC, QUE2FH, and QUESH exhibit the property of partial activation as compared to the overexpressive level of rosiglitazone. Consistently, these QDs also suppress EMT process by markedly downregulating the levels of mesenchymal markers (Snail, Slug, and zinc finger E‐box binding homeobox 1) and concomitant upregulation of epithelial marker (E‐cadherin).

show abstract

Strong Short‐Range Cooperativity in Hydrogen‐Bond Chains

et al. 2017

View full text Add to dashboard Cite

Chains of hydrogen bonds such as those found in water and proteins are often presumed to be more stable than the sum of the individual Hbonds.However,the energetics of cooperativity are complicated by solvent effects and the dynamics of intermolecular interactions,m eaning that information on cooperativity typically is derived from theory or indirect structural data. Herein, we present direct measurements of energetic cooperativity in an experimental system in which the geometry and the number of Hbonds in achain were systematically controlled. Strikingly,w ef ound that adding asecond H-bond donor to form achain can almost double the strength of the terminal Hbond, while further extensions have little effect. The experimental observations add weight to computations whichh ave suggested that strong, but shortrange cooperative effects mayo ccur in H-bond chains.Chainsofhydrogenbondsareprevalentstructural motifs in supramolecular and biological systems. Hbonds are widely proposed to exhibit positive cooperativity, [1] which may be manifested by acombination of conformational [1,2] and electronic effects that may make ac hain more stable than the sum of its parts.[3] Such cooperative effects have been shown to influence reactivity, [4] to contribute to the structure,i nteractions,a nd properties of biomolecules and materials, [5] and to facilitate the communication of chemical information.[6] Hbonded water clusters and chains have been isolated in the solid state [7] and studied experimentally in both liquid and gas phases.[8] Although many nanoscale and bulk properties may be influenced by the cooperativity of H-bond networks,itisnot possible to directly quantify interaction energies from structural or vibrational characteristics.I na ddition, discussion of the relative contributions of electrostatics,p olarization, and covalencyi nHbond cooperativity [5b, 9] is further exacerbated by the challenge of considering the influence of the surrounding solvent.Herein, we have employed synthetic molecular balances [10] to directly measure the effect of H-bond-chain length on the strength of H-bonding interactions in solution. At the outset of our investigation we identified the series of phenol, catechol, and pyrogallol ( Figure 1B)a sapertinent model system for examining cooperativity in H-bond chains.Indeed, H-bond chains have previously been proposed to contribute to the supramolecular properties of catechol and pyrogallol derivatives. [3b, 11] We reasoned that the pre-organization and proximity of the intramolecular H-bond donors and acceptors in this series of compounds would minimize conformational entropic effects to allow examination of cooperative electronic influences.I nitially we measured the experimental complexation Gibbs energies of phenol, catechol, and pyrogallol with the strong H-bond acceptor tri-n-butylphosphine oxide using 31 PNMR spectroscopy.T he binding energies became more favorable as the number of OH groups was increased ( Figure 1A). Such atrend could be rationalized by cooperative e...

show abstract

Regulation of protein-ligand binding affinity by hydrogen bond pairing

Abstract: Receptor-ligand H-bond pairings have evolved to promote high-affinity binding by reducing competitive interference with water.

Cited by 601 publications

References 54 publications

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

Design, Synthesis, and Biological Evaluation of Novel Quercetin Derivatives as PPAR‐γ Partial Agonists by Modulating Epithelial–Mesenchymal Transition in Lung Cancer Metastasis

Strong Short‐Range Cooperativity in Hydrogen‐Bond Chains

Contact Info

Product

Resources

About