Rational reduction of the conformational space of a siderophore analog through nonbonded interactions: the role of entropy in enterobactin

1993 ◽  
Vol 115 (14) ◽  
pp. 6466-6467 ◽  
Author(s):  
T. D. P. Stack ◽  
Zhiguo Hou ◽  
Kenneth N. Raymond
Keyword(s):  
Conformational Space ◽  
Nonbonded Interactions ◽  
Siderophore Analog

Tosylate salts of the anticancer drug lapatinib

2013 ◽  
Vol 69 (12) ◽  
pp. 1516-1523 ◽  
Author(s):  
K. Ravikumar ◽  
B. Sridhar ◽  
Jagadeesh Babu Nanubolu ◽  
A. K. S. Bhujanga Rao ◽  
R. Jyothiprasad
Keyword(s):  
Solid State ◽  
Hydrogen Bonds ◽  
Physicochemical Properties ◽  
Anticancer Drug ◽  
Ring System ◽  
Nonbonded Interactions ◽  
One Dimensional ◽  
Drug Products ◽  
Ring Motif

Two tosylate salts of an anticancer drug lapatinib,viz. a monotosylate [systematic name: ({5-[4-({3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino)quinazolin-6-yl]furan-2-yl}methyl)[2-(methylsulfonyl)ethyl]azanium 4-methylbenzenesulfonate], C29H27ClFN4O4S+·C7H7O3S−, (I), and a ditosylate [systematic name: 4-({3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino)-6-]5-({[2-(methylsulfonyl)ethyl]azaniumyl}methyl)furan-2-yl[quinazolin-1-ium bis(4-methylbenzenesulfonate)], C29H28ClFN4O4S2+·2C7H7O3S−, (II), were obtained during crystallization attempts for polymorphism. In both structures, the lapatinib cation is in a distorted U-like conformation and the tosylate anion is clamped between the aniline N atom and methylamine N atom through N—H...O hydrogen bonds, forming anR22(15) ring motif. The 4-anilinoquinazoline ring system is essentially planar in (I), while it is twisted in (II), controlled by an intramolecular C—H...N interaction. In (I), alternating cations and anions are linked by N—H...O hydrogen bonds intoC22(6) chains. These chains are linked by cations in a helical manner. The presence of the additional tosylate anion in (II) results in the formation of one-dimensional tapes of fused hydrogen-bonded rings through N—H...O and C—H...O interactions. These studies augment our understanding of the role of nonbonded interactions in the solid state, which is useful for correlation to the physicochemical properties of drug products.

Vibrational Relaxation and Energy Migration of N-Methylacetamide in Water: The Role of Nonbonded Interactions

2015 ◽  
Vol 119 (7) ◽  
pp. 3112-3122 ◽  
Author(s):  
Pierre-André Cazade ◽  
Florent Hédin ◽  
Zhen-Hao Xu ◽  
Markus Meuwly
Keyword(s):  
Vibrational Relaxation ◽  
Energy Migration ◽  
Nonbonded Interactions

scholarly journals Point Mutations at a Key Site Alter the Cytochrome P450 OleP Structural Dynamics

Biomolecules ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 55
Author(s):  
Linda Celeste Montemiglio ◽  
Elena Gugole ◽  
Ida Freda ◽  
Cécile Exertier ◽  
Lucia D’Auria ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Substrate Binding ◽  
Point Mutations ◽  
Conformational Space ◽  
Amino Acid Side Chain ◽  
Dynamic Simulations ◽  
Substrate Protein ◽  
Contact Points ◽  
Solvent Molecules

Substrate binding to the cytochrome P450 OleP is coupled to a large open-to-closed transition that remodels the active site, minimizing its exposure to the external solvent. When the aglycone substrate binds, a small empty cavity is formed between the I and G helices, the BC loop, and the substrate itself, where solvent molecules accumulate mediating substrate-enzyme interactions. Herein, we analyzed the role of this cavity in substrate binding to OleP by producing three mutants (E89Y, G92W, and S240Y) to decrease its volume. The crystal structures of the OleP mutants in the closed state bound to the aglycone 6DEB showed that G92W and S240Y occupied the cavity, providing additional contact points with the substrate. Conversely, mutation E89Y induces a flipped-out conformation of this amino acid side chain, that points towards the bulk, increasing the empty volume. Equilibrium titrations and molecular dynamic simulations indicate that the presence of a bulky residue within the cavity impacts the binding properties of the enzyme, perturbing the conformational space explored by the complexes. Our data highlight the relevance of this region in OleP substrate binding and suggest that it represents a key substrate-protein contact site to consider in the perspective of redirecting its activity towards alternative compounds.

scholarly journals Phospho-Mimetic Mutation at Ser602 Inactivates Human TRPA1 Channel

2020 ◽  
Vol 21 (21) ◽  
pp. 7995
Author(s):  
Kristyna Barvikova ◽  
Ivan Barvik ◽  
Viktor Sinica ◽  
Lucie Zimova ◽  
Viktorie Vlachova
Keyword(s):  
Intracellular Signaling ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Conformational Space ◽  
Signaling Cascades ◽  
Post Translational Modifications ◽  
Allosteric Coupling ◽  
Structural Impact ◽  
Transient Receptor

The Transient Receptor Potential Ankyrin 1 (TRPA1) channel is an integrative molecular sensor for detecting environmental irritant compounds, endogenous proalgesic and inflammatory agents, pressure, and temperature. Different post-translational modifications participate in the discrimination of the essential functions of TRPA1 in its physiological environment, but the underlying structural bases are poorly understood. Here, we explored the role of the cytosolic N-terminal residue Ser602 located near a functionally important allosteric coupling domain as a potential target of phosphorylation. The phosphomimetic mutation S602D completely abrogated channel activation, whereas the phosphonull mutations S602G and S602N produced a fully functional channel. Using mutagenesis, electrophysiology, and molecular simulations, we investigated the possible structural impact of a modification (mutation or phosphorylation) of Ser602 and found that this residue represents an important regulatory site through which the intracellular signaling cascades may act to reversibly restrict or “dampen” the conformational space of the TRPA1 channel and promote its transitions to the closed state.

Role of Nonbonded Interactions in Determining Solution Conformations of Oligosaccharides

1994 ◽  
pp. 252-268 ◽  
Author(s):  
Robert J. Woods ◽  
Bert Fraser-Reid ◽  
Raymond A. Dwek ◽  
Christopher J. Edge
Keyword(s):  
Nonbonded Interactions ◽  
Solution Conformations

Femtosecond Spectroscopy of a 13-Demethylrhodopsin Visual Pigment Analogue:  The Role of Nonbonded Interactions in the Isomerization Process

1996 ◽  
Vol 100 (43) ◽  
pp. 17388-17394 ◽  
Author(s):  
Qing Wang ◽  
Gerd G. Kochendoerfer ◽  
Robert W. Schoenlein ◽  
Peter J. E. Verdegem ◽  
Johan Lugtenburg ◽  
...  
Keyword(s):  
Visual Pigment ◽  
Femtosecond Spectroscopy ◽  
Nonbonded Interactions ◽  
Isomerization Process

scholarly journals Designing single-crystal-to-single-crystal Diels–Alder reactions: the role of nonbonded interactions

2016 ◽  
Vol 72 (a1) ◽  
pp. s130-s130
Author(s):  
Demetrius C. Levendis ◽  
Sanaz Khorasani ◽  
Delbert Botes ◽  
Manuel A. Fernandes
Keyword(s):  
Single Crystal ◽  
Diels Alder ◽  
Nonbonded Interactions

scholarly journals The Role of Conformational Dynamics in abacavir-Induced Hypersensitivity Syndrome

2017 ◽  
Author(s):  
James Fodor ◽  
Blake T. Riley ◽  
Itamar Kass ◽  
Ashley M. Buckle ◽  
Natalie A. Borg
Keyword(s):  
Drug Hypersensitivity ◽  
Conformational Dynamics ◽  
Human Leukocyte ◽  
Immune Deficiency Syndrome ◽  
Hypersensitivity Syndrome ◽  
Conformational Space ◽  
Hypersensitivity Reactions ◽  
Drug Induced ◽  
Diverse Range

AbstractAbacavir is an antiretroviral drug used to reduce human immunodeficiency virus (HIV) replication and decrease the risk of developing acquired immune deficiency syndrome (AIDS). However, its therapeutic value is diminished by the fact that it is associated with drug hypersensitivity reactions in up to 8% of treated patients. This hypersensitivity is strongly associated with patients carrying human leukocyte antigen (HLA)-B*57:01, but not patients carrying closely related alleles. Abacavir’s specificity to HLA-B*57:01 is attributed to its binding site within the peptide-binding cleft and subsequent influence of the repertoire of peptides that can bind HLA-B*57:01. To further our understanding of abacavir-induced hypersensitivity we used molecular dynamics (MD) to analyze the dynamics of three different peptides bound to HLA-B*57:01 in the presence and absence of abacavir or abacavir analogues. We found that abacavir and associated peptides bind to HLA-B*57:01 in a highly diverse range of conformations that are not apparent from static crystallographic snapshots. Further, the presence of abacavir has a direct impact on the dynamics and the conformational space available to peptides bound to HLA-B*57:01, likely influencing abacavir-induced immune self-reactivity. Our results support hypersensitivity models in which abacavir-binding alters the equilibrium proportions of neopeptide conformations in a manner favourable to TCR binding. Our findings highlight the need to also consider the role of dynamics in understanding drug-induced hypersensitivities at the molecular and mechanistic level. This additional insight can help inform the chemical modification of abacavir to prevent hypersensitivity reactions in HLA-B*57:01+ HIV patients whilst retaining potent antiretroviral activity.

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