Thermodynamic and Structural Characterization of Halogen Bonding in Protein–Ligand Interactions: A Case Study of PDE5 and Its Inhibitors

2014 ◽  
Vol 57 (8) ◽  
pp. 3588-3593 ◽  
Author(s):  
Jing Ren ◽  
Yang He ◽  
Wuyan Chen ◽  
Tiantian Chen ◽  
Guan Wang ◽  
...  
Keyword(s):  
Structural Characterization ◽  
Halogen Bonding ◽  
Protein Ligand Interactions ◽  
Ligand Interactions

A knowledge-based halogen bonding scoring function for predicting protein-ligand interactions

2013 ◽  
Vol 19 (11) ◽  
pp. 5015-5030 ◽  
Author(s):  
Yingtao Liu ◽  
Zhijian Xu ◽  
Zhuo Yang ◽  
Kaixian Chen ◽  
Weiliang Zhu
Keyword(s):  
Scoring Function ◽  
Halogen Bonding ◽  
Knowledge Based ◽  
Protein Ligand Interactions ◽  
Ligand Interactions

scholarly journals Halogen Bonding: An Underestimated Player in Membrane–drug Interactions

2020 ◽  
Author(s):  
Rafael Nunes ◽  
Diogo Vila Viçosa ◽  
Paulo J. Costa
Keyword(s):  
Drug Discovery ◽  
Chemical Space ◽  
Noncovalent Interactions ◽  
Halogen Bonding ◽  
Lewis Bases ◽  
Protein Ligand Interactions ◽  
Biochemical Systems ◽  
Ligand Interactions ◽  
Dynamics Simulations

<div>Halogen bonds (HaBs) are noncovalent interactions where halogen atoms act as electrophilic species interacting with Lewis bases. These interactions are relevant in biochemical systems being increasingly explored in drug discovery, mainly to modulate protein–ligand interactions. In this work, we report evidence for the existence of HaB-mediated halogen–phospholipid recognition phenomena as our molecular dynamics simulations support the existence of favorable interactions between halobenzene derivatives and both phosphate (PO) or ester (CO) oxygen acceptors from model phospholipid bilayers, thus providing insights into the role of HaBs in driving the permeation of halogenated drug like molecules across biological membranes. This represents a relevant molecular mechanism, previously overlooked, determining the pharmacological activity of halogenated molecules with implications in drug discovery and development, a place where halogenated molecules account for a significant part of the chemical space. Our data also shows that, as the ubiquitous hydrogen bond, HaBs should be accounted for in the development of membrane permeability models.</div>

scholarly journals Characterization of protein-ligand binding interactions of enoyl-ACP reductase (FabI) by native MS reveals allosteric effects of coenzymes and the inhibitor triclosan

2019 ◽  
Author(s):  
P. Matthew Joyner ◽  
Denise P. Tran ◽  
Muhammad A. Zenaidee ◽  
Joseph A. Loo
Keyword(s):  
Fatty Acid Synthase ◽  
Antibacterial Drug ◽  
Allosteric Effect ◽  
The Past ◽  
Protein Ligand Interactions ◽  
Native Ms ◽  
Ligand Interactions ◽  
Enoyl Acp Reductase ◽  
The Subject

AbstractThe enzyme enoyl-ACP reductase (also called FabI in bacteria) is an essential member of the fatty acid synthase II pathway in plants and bacteria. This enzyme is the target of the antibacterial drug triclosan and has been the subject of extensive studies for the past 20 years. Despite the large number of reports describing the biochemistry of this enzyme, there have been no studies that provided direct observation of the protein and its various ligands. Here we describe the use of native MS to characterize the protein-ligand interactions of FabI with its coenzymes NAD+ and NADH and with the inhibitor triclosan. Measurements of the gas-phase affinities of the enzyme for these ligands yielded values that are in close agreement with solution-phase affinity measurements. Additionally, FabI is a homotetramer and we were able to measure the affinity of each subunit for each coenzyme, which revealed that both coenzymes exhibit a positive homotropic allosteric effect. An allosteric effect was also observed in association with the inhibitor triclosan. These observations provide new insights into this well-studied enzyme and suggest that there may still be gaps in the existing mechanistic models that explain FabI inhibition.

NMR investigation of protein–ligand interactions for G-protein coupled receptors

2019 ◽  
Vol 11 (14) ◽  
pp. 1811-1825 ◽  
Author(s):  
Claire Raingeval ◽  
Isabelle Krimm
Keyword(s):  
Conformational Changes ◽  
Functional Characterization ◽  
Allosteric Modulation ◽  
G Protein Coupled Receptors ◽  
Nmr Studies ◽  
Protein Ligand Interactions ◽  
Ligand Interactions ◽  
Therapeutic Compounds ◽  
G Protein Coupled

In this review, we report NMR studies of ligand–GPCR interactions, including both ligand-observed and protein-observed NMR experiments. Published studies exemplify how NMR can be used as a powerful tool to design novel GPCR ligands and investigate the ligand-induced conformational changes of GPCRs. The strength of NMR also lies in its capability to explore the diverse signaling pathways and probe the allosteric modulation of these highly dynamic receptors. By offering unique opportunities for the identification, structural and functional characterization of GPCR ligands, NMR will likely play a major role for the generation of novel molecules both as new tools for the understanding of the GPCR function and as therapeutic compounds for a large diversity of pathologies.

scholarly journals Site-Resolved and Quantitative Characterization of Very Weak Protein–Ligand Interactions

2019 ◽  
Vol 14 (7) ◽  
pp. 1398-1402 ◽  
Author(s):  
Brian Fuglestad ◽  
Nicole E. Kerstetter ◽  
A. Joshua Wand
Keyword(s):  
Quantitative Characterization ◽  
Protein Ligand Interactions ◽  
Ligand Interactions

A quantum mechanics-based halogen bonding scoring function for protein-ligand interactions

2015 ◽  
Vol 21 (6) ◽  
Author(s):  
Zhuo Yang ◽  
Yingtao Liu ◽  
Zhaoqiang Chen ◽  
Zhijian Xu ◽  
Jiye Shi ◽  
...  
Keyword(s):  
Quantum Mechanics ◽  
Scoring Function ◽  
Halogen Bonding ◽  
Protein Ligand Interactions ◽  
Ligand Interactions

Halogen bonding: an underestimated player in membrane-ligand interactions

2021 ◽  
Author(s):  
Rafael Nunes ◽  
Diogo Vila Viçosa ◽  
Paulo J. Costa
Keyword(s):  
Drug Discovery ◽  
Chemical Space ◽  
Noncovalent Interactions ◽  
Biological Membrane ◽  
Halogen Bonding ◽  
Membrane Insertion ◽  
Protein Ligand Interactions ◽  
Biochemical Systems ◽  
Ligand Interactions ◽  
Dynamics Simulations

<div>Halogen bonds (XBs) are noncovalent interactions where halogen atoms act as electrophilic species interacting with Lewis bases. These interactions are relevant in biochemical systems being increasingly explored in drug discovery, mainly to modulate protein–ligand interactions, but are also found in engineered protein or nucleic acid systems. In this work, we report direct evidence for the existence of XBs in the context of biological membrane systems thus expanding the scope of application of these interactions. Indeed, our molecular dynamics simulations show the presence of favorable interactions between halobenzene derivatives and both phosphate or ester oxygen acceptors from model phospholipid bilayers, thus supporting the existence of XB mediated phospholipid–halogen recognition phenomena influencing the membrane insertion profile of the ligands and their orientational preferences. This represents a relevant interaction, previously overlooked, eventually determining the pharmacological or toxicological activity of halogenated compounds and hence with potential implications in drug discovery and development, a place where such species account for a significant part of the chemical space. We also provide insights into a potential role for XBs in water-to membrane insertion of halogenated ligands as XBs are systematically observed during this process. Therefore, our data strongly suggests that, as the ubiquitous hydrogen bond, XBs should be accounted for in the development of membrane partition models.</div>

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