Identification of the Binding Modes ofN-Phenylphthalimides Inhibiting Bacterial Thymidylate Synthase through X-Ray Crystallography Screening

2011 ◽  
Vol 54 (15) ◽  
pp. 5454-5467 ◽  
Author(s):  
Stefano Mangani ◽  
Laura Cancian ◽  
Rosalida Leone ◽  
Cecilia Pozzi ◽  
Sandra Lazzari ◽  
...  
Keyword(s):  
Thymidylate Synthase ◽  
Binding Modes ◽  
X Ray ◽  
X Ray Crystallography

Virtual Screening and X-ray Crystallography Identify Non-Substrate Analog Inhibitors of Flavin-Dependent Thymidylate Synthase

2016 ◽  
Vol 59 (19) ◽  
pp. 9269-9275 ◽  
Author(s):  
Rosaria Luciani ◽  
Puneet Saxena ◽  
Sachin Surade ◽  
Matteo Santucci ◽  
Alberto Venturelli ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Thymidylate Synthase ◽  
X Ray ◽  
X Ray Crystallography ◽  
Substrate Analog

scholarly journals Multiple binding modes of a small molecule to human Keap1 revealed by X-ray crystallography and molecular dynamics simulation

FEBS Open Bio ◽  
2015 ◽  
Vol 5 (1) ◽  
pp. 557-570 ◽  
Author(s):  
Mikiya Satoh ◽  
Hajime Saburi ◽  
Tomoyuki Tanaka ◽  
Yoshinori Matsuura ◽  
Hisashi Naitow ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Small Molecule ◽  
Dynamics Simulation ◽  
Binding Modes ◽  
X Ray ◽  
X Ray Crystallography ◽  
Multiple Binding

scholarly journals Structural basis for the binding of SNAREs to the multisubunit tethering complex Dsl1

2020 ◽  
Author(s):  
Sophie M. Travis ◽  
Kevin DAmico ◽  
I-Mei Yu ◽  
Safraz Hamid ◽  
Gabriel Ramirez-Arellano ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
Relative Orientation ◽  
Snare Complex ◽  
Structural Basis ◽  
Binding Modes ◽  
Range Interaction ◽  
X Ray ◽  
X Ray Crystallography ◽  
Long Range Interaction ◽  
Target Membrane

AbstractMultisubunit tethering complexes (MTCs) are large (250 to >750 kDa), conserved macromolecular machines that are essential for SNARE-mediated membrane fusion in all eukaryotes. MTCs are thought to function as organizers of membrane trafficking, mediating the initial, long-range interaction between a vesicle and its target membrane and promoting the formation of membrane-bridging SNARE complexes. Previously, we reported the structure of the Dsl1 complex, the simplest known MTC, which is essential for COPI-mediated transport from the Golgi to the endoplasmic reticulum (ER). This structure suggested how the Dsl1 complex might function to tether a vesicle to its target membrane by binding at one end to the COPI coat and at the other end to ER SNAREs. Here, we use x-ray crystallography to investigate these Dsl1-SNARE interactions in greater detail. The Dsl1 complex comprises three subunits that together form a two-legged structure with a central hinge. Our results show that distal regions of each leg bind N-terminal Habc domains of the ER SNAREs Sec20 (a Qb-SNARE) and Use1 (a Qc-SNARE). The observed binding modes appear to anchor the Dsl1 complex to the ER target membrane while simultaneously ensuring that both SNAREs are in open conformations with their SNARE motifs available for assembly. The proximity of the two SNARE motifs, and therefore their ability to enter the same SNARE complex, depends on the relative orientation of the two Dsl1 legs.

scholarly journals X-Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A2A Adenosine Receptor Antagonists

2019 ◽  
Author(s):  
Willem Jespers ◽  
Grégory Verdon ◽  
Jhonny Azuaje ◽  
maria majellaro ◽  
Henrik Keränen ◽  
...  
Keyword(s):  
Free Energy ◽  
Adenosine Receptor ◽  
Free Energy Calculations ◽  
Binding Modes ◽  
A2a Adenosine Receptor ◽  
Binding Model ◽  
Energy Calculations ◽  
X Ray ◽  
X Ray Crystallography ◽  
Pharmacological Data

<div> <div> <div> <p>Nowadays, rigorous free energy calculations are routinely considered in pharmaceutical design strategies. One typical sce- nario is the lead-optimization based on well-defined protein-ligand binding modes, inferred by pharmacological data in com- putational models and ultimately revealed by structural data. In this work, we reveal the molecular determinants of antago- nist binding to the adenosine A2A adenosine receptor (AR), an emerging target in immuno-oncology, via a robust protocol that connects structural and pharmacological data through free energy perturbation (FEP) calculations. Eight A2AAR binding site mutations from biophysical mapping experiments were initially analyzed with FEP simulations of each side-chain mutation, performed on alternate binding modes previously proposed in the literature. The results strongly suggested that only one binding mode could explain this experimental data, which was used to subsequently design a series of 11 chromone deriva- tives. The experimental affinities of these new compounds were linked through a cycle of ligand-FEP calculations around selected ligand pairs, which allowed the identification of the optimal positioning of the different chemical substituents in the proposed binding model. Subsequent X-ray crystallography of the A2AAR with a low and high affinity chromone derivative confirmed the predicted binding orientation, and provided new insights in the role of the explored substituents in the chro- </p> </div> </div> <div> <div> <p>mone scaffold. </p> </div> </div> </div>

scholarly journals Comparison of Orexin 1 and Orexin 2 Ligand Binding Modes Using X-ray Crystallography and Computational Analysis

2019 ◽  
Vol 63 (4) ◽  
pp. 1528-1543 ◽  
Author(s):  
Mathieu Rappas ◽  
Ammar A. E. Ali ◽  
Kirstie A. Bennett ◽  
Jason D. Brown ◽  
Sarah J. Bucknell ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Computational Analysis ◽  
Binding Modes ◽  
X Ray ◽  
X Ray Crystallography

scholarly journals An NMR study of mixed, tartrate-containing TiIV complexes

1995 ◽  
Vol 73 (3) ◽  
pp. 401-413 ◽  
Author(s):  
Pierre G. Potvin ◽  
Benjamin G. Fieldhouse
Keyword(s):  
Product Formation ◽  
Primary Amines ◽  
Binding Modes ◽  
Minor Components ◽  
Tertiary Amines ◽  
X Ray ◽  
X Ray Crystallography ◽  
Nmr Study ◽  
The Rich ◽  
C Nmr

The reactions of amines and amino alcohols with diisopropyl or diethyl R,R- or S,S-tartrate and Ti(OiPr)4 were examined by 1H and 13C NMR to obtain and characterize nonfluxional complexes with the tartrate units in novel binding modes. The mildly acidic 8-hydroxyquinoline and N-phenyl-N-benzoylhydroxylamine selectively formed the products of a double OiPr substitution, Ti2(tartrate)2(ligand)2(OiPr)2, and the products of double tartrate substitution, Ti(ligand)2(OiPr)2, while 2,4-pentanedione formed only the latter Basic amino alkanols formed diastereomerically pure Ti2(tartrate)2(aminoalkoxide)(OiPr)3 species. N,N-Dimethyl-2-aminoethanol (Hdmae) also and uniquely formed monomeric Ti(tartrate)2(Hdmae)2 species that could be described as doubly zwitterionic. Secondary or tertiary amines formed triply C2-symmetric Ti3(tartrate)4(amine)2(OiPr)4 assemblies. Some minor components were believed to be μ-OiPr species. All mixed complexes except Ti(tartrate)2(Hdmae)2 contained chelating and bridging tartrate units, without coordination by ester carbonyls. A nonchelating, nonbridging tartrate unit was also present in the amino alcohol cases. Primary amines, aromatic amines, and hydrazines all failed to provide identifiable complexes. As well, N,N-dibenzylhydroxylamine failed to generate in solution the complex that had previously been characterized by X-ray crystallography. Amidst the rich chemistry of TiIV-tartrate systems, the evident selectivities in product formation were ascribed to macro-ring closures that are specifically directed by the electronic nature of the addend. Transient OiPr-bridged intermediates were also implicated. Keywords: mixed TiIV alkoxides, chiral TiIV alkoxides, enantiospecific complexation.

Metabolic intervention targeting 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) using a structure-based design.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13518-e13518
Author(s):  
Lars Ährlund-Richter ◽  
Katarina Färnegårdh ◽  
Elisee Wiita ◽  
Mattias Jönsson ◽  
Carina Norström ◽  
...  
Keyword(s):  
Cell Growth ◽  
High Throughput ◽  
High Throughput Screening ◽  
Structural Information ◽  
Human Cancer ◽  
Isothermal Calorimetry ◽  
Binding Pocket ◽  
Binding Modes ◽  
X Ray ◽  
X Ray Crystallography

e13518 Background: By producing fructose-2,6-bisphosphate, PFKFB3 functions as an activator of anaerobic glycolysis. PFKFB3 is both over expressed and over activated in many of the types of human cancer. Specific inhibition of the PFKFB3 enzyme results in a reduction in metabolism and cell growth in oxygen-deficient cancer environments. Methods: High-throughput screening. Medicinal Chemistry. Structure-Based Drug Design, X-ray Crystallography. NMR. Isothermal Calorimetry. Dynamic Light Scatttering. ADME. Results: A high-throughput screening of 50.000 selected compounds, by means of a biochemical assay, generated 105 hits including both ATP-and non-ATP competitive hits as identified by NMR binding experiments. The latter type was prioritized and two hits with a similar “ring-linker-ring structure” were selected for further expansions. Interestingly, although structurally similar, the two hits were found by means of X-ray crystallography to exhibit different binding modes within the fructose pocket. Based on their respective binding mode, two chemical series were developed displaying different ADME properties and PFKFB isoenzyme selectivity. Calorimetry verified a reversible strong enthalpy driven, direct binding for both chemical series. A third chemical series was developed towards yet another unoccupied binding pocket within the fructose-site, yielding a 5-fold increase in potency. Strong interactions within the new pocket were confirmed using X-ray crystallography. Our PFKFB3 inhibitors were shown to reduce tumor cell growth in vitro and to exhibit combinatory effects with Cisplatin. Conclusions: We have targeted the fructose-binding pocket of PFKFB3, developed compounds with nM binding potency and have gained a detailed understanding of SAR via structural information. The structure-based analysis has provided a good understanding of the molecular interactions, which is important for further biological/clinical positioning: e.g., combination with chemotherapy, optimization of PK properties and proof of principle in vivo.

scholarly journals X-Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A2A Adenosine Receptor Antagonists

2019 ◽  
Author(s):  
Willem Jespers ◽  
Grégory Verdon ◽  
Jhonny Azuaje ◽  
maria majellaro ◽  
Henrik Keränen ◽  
...  
Keyword(s):  
Free Energy ◽  
Adenosine Receptor ◽  
Free Energy Calculations ◽  
Binding Modes ◽  
A2a Adenosine Receptor ◽  
Binding Model ◽  
Energy Calculations ◽  
X Ray ◽  
X Ray Crystallography ◽  
Pharmacological Data

<div> <div> <div> <p>Nowadays, rigorous free energy calculations are routinely considered in pharmaceutical design strategies. One typical sce- nario is the lead-optimization based on well-defined protein-ligand binding modes, inferred by pharmacological data in com- putational models and ultimately revealed by structural data. In this work, we reveal the molecular determinants of antago- nist binding to the adenosine A2A adenosine receptor (AR), an emerging target in immuno-oncology, via a robust protocol that connects structural and pharmacological data through free energy perturbation (FEP) calculations. Eight A2AAR binding site mutations from biophysical mapping experiments were initially analyzed with FEP simulations of each side-chain mutation, performed on alternate binding modes previously proposed in the literature. The results strongly suggested that only one binding mode could explain this experimental data, which was used to subsequently design a series of 11 chromone deriva- tives. The experimental affinities of these new compounds were linked through a cycle of ligand-FEP calculations around selected ligand pairs, which allowed the identification of the optimal positioning of the different chemical substituents in the proposed binding model. Subsequent X-ray crystallography of the A2AAR with a low and high affinity chromone derivative confirmed the predicted binding orientation, and provided new insights in the role of the explored substituents in the chro- </p> </div> </div> <div> <div> <p>mone scaffold. </p> </div> </div> </div>

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