Design, synthesis, and kinetic evaluation of high-affinity FKBP ligands and the X-ray crystal structures of their complexes with FKBP12

1993 ◽  
Vol 115 (22) ◽  
pp. 9925-9938 ◽  
Author(s):  
Dennis A. Holt ◽  
Juan I. Luengo ◽  
Dennis S. Yamashita ◽  
Hye Ja Oh ◽  
Arda L. Konialian ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Design Synthesis ◽  
Kinetic Evaluation ◽  
X Ray ◽  
High Affinity

scholarly journals High Consistency of Structure-Based Design and X-Ray Crystallography: Design, Synthesis, Kinetic Evaluation and Crystallographic Binding Mode Determination of Biphenyl-N-acyl-β-d-Glucopyranosylamines as Glycogen Phosphorylase Inhibitors

Molecules ◽  
2019 ◽  
Vol 24 (7) ◽  
pp. 1322 ◽  
Author(s):  
Thomas Fischer ◽  
Symeon M. Koulas ◽  
Anastasia S. Tsagkarakou ◽  
Efthimios Kyriakis ◽  
George A. Stravodimos ◽  
...  
Keyword(s):  
Glycogen Phosphorylase ◽  
Catalytic Mechanism ◽  
Liver Glycogen ◽  
Binding Mode ◽  
Structural Water ◽  
Design Synthesis ◽  
Kinetic Evaluation ◽  
X Ray ◽  
X Ray Crystallography ◽  
Design And Synthesis

Structure-based design and synthesis of two biphenyl-N-acyl-β-d-glucopyranosylamine derivatives as well as their assessment as inhibitors of human liver glycogen phosphorylase (hlGPa, a pharmaceutical target for type 2 diabetes) is presented. X-ray crystallography revealed the importance of structural water molecules and that the inhibitory efficacy correlates with the degree of disturbance caused by the inhibitor binding to a loop crucial for the catalytic mechanism. The in silico-derived models of the binding mode generated during the design process corresponded very well with the crystallographic data.

scholarly journals Design, synthesis, and X-ray crystal structures of 2,4-diaminofuro[2,3-d]pyrimidines as multireceptor tyrosine kinase and dihydrofolate reductase inhibitors

2009 ◽  
Vol 17 (20) ◽  
pp. 7324-7336 ◽  
Author(s):  
Aleem Gangjee ◽  
Wei Li ◽  
Lu Lin ◽  
Yibin Zeng ◽  
Michael Ihnat ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Crystal Structures ◽  
Dihydrofolate Reductase ◽  
Design Synthesis ◽  
X Ray ◽  
Reductase Inhibitors ◽  
Dihydrofolate Reductase Inhibitors

X-Ray structures and binding properties of molecular clips based on diethoxycarbonyl glycoluril

2007 ◽  
Vol 85 (9) ◽  
pp. 586-591 ◽  
Author(s):  
Bao H Zhou ◽  
Li P Cao ◽  
Guo D Yin ◽  
M Gao ◽  
An X Wu
Keyword(s):  
Crystal Structure ◽  
Crystal Structures ◽  
Good Evidence ◽  
Binding Properties ◽  
X Ray ◽  
H Nmr ◽  
Binding Behavior ◽  
High Affinity ◽  
Molecular Clips

The crystal structures of two molecular clips derived from diethoxycarbonyl glycoluril were reported. Their unique binding behavior towards hydroquinone, which is different from Nolte's clips (high affinity for resorcinol), has been characterized through 1H NMR and IR. Job-plot analyses provide good evidence of a 1:1 stoichiometry for the complexes.Key words: crystal structure, molecular clips, binding properties

scholarly journals Heteroaryl Chalcones: Design, Synthesis, X-ray Crystal Structures and Biological Evaluation

Molecules ◽  
2013 ◽  
Vol 18 (10) ◽  
pp. 12707-12724 ◽  
Author(s):  
C. Kumar ◽  
Wan-Sin Loh ◽  
Chin Ooi ◽  
Ching Quah ◽  
Hoong-Kun Fun
Keyword(s):  
Crystal Structures ◽  
Biological Evaluation ◽  
Design Synthesis ◽  
X Ray

scholarly journals 882 Selective affinity-enhanced T cell receptor bispecific targeting of KRAS G12D neoantigen driven cancers

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A924-A924
Author(s):  
Andrew Whale ◽  
Andrew Poole ◽  
Vijaykumar Karuppiah ◽  
Annabelle Hartt ◽  
Jaafar Haidar ◽  
...  
Keyword(s):  
T Cell ◽  
Crystal Structures ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Receptor ◽  
Single Amino Acid ◽  
X Ray ◽  
High Affinity ◽  
T Cell Clone ◽  
Wide Range

BackgroundKRAS is the most frequently mutated oncogene, yet mutant KRAS has historically been a challenging target for conventional small molecule drug development. Tumour specific neoantigen peptides derived from KRAS are presented by cell surface human leucocyte antigens (HLA) and form a class of shared, tumour-specific antigens that are attractive targets for immunotherapy.MethodsA T cell clone that specifically recognizes the most common KRAS G12D mutant presented as a peptide in the context of HLA-A*11:01 was isolated from healthy donor PBMCs. The affinity of the respective T cell receptor (TCR) was enhanced by phage display and the x-ray crystal structures of the affinity-enhanced TCR bound to HLA presenting mutant KRAS G12D and wildtype (KRAS WT) peptides were solved. We used structural, biochemical, and computational approaches to investigate the molecular interactions underlying TCR selectivity for mutant KRAS G12D. Finally, the high affinity TCR was engineered into a soluble T cell engaging ImmTAC (Immune mobilizing monoclonal TCR Against Cancer) molecule, IMC-KRAS-G12D, and in vitro cell-based assays were performed to evaluate its potency and selectivity.ResultsThe affinity of the engineered TCR was enhanced by a million-fold and demonstrated remarkable ability to distinguish between KRAS G12D and KRAS WT peptide presented by HLA-A*11:01. X-ray crystal structures demonstrate that TCR binding is almost identical between KRAS G12D and KRAS WT despite a binding affinity difference of >4000 fold. The mutant residue G12D is buried into the HLA peptide binding groove and acts as a secondary anchor, making it inaccessible to the TCR. Thermodynamic analysis of TCR-HLA interaction combined with molecular dynamics simulations indicates a novel mechanism of peptide selectivity, mediated by an indirect energetic mechanism driven by an induced fit in the peptide upon TCR binding. In functional assays, this molecular differentiation translated into biological specificity with IMC-KRAS-G12D mediating T cell activation in response to cells pulsed with or expressing KRAS G12D but not KRAS WT. Furthermore, IMC-KRAS-G12D was able to redirect T cell cytotoxicity towards target KRAS G12D presenting colon cancer cells, while sparing normal colon epithelial cellsConclusionsWe developed a high affinity TCR bispecific with exquisite specificity towards a common shared neoantigen, KRAS G12D, that is a relevant therapeutic target in a wide range of cancers. These findings reveal a novel molecular mechanism for TCR selectivity for a neoantigen that differs from self-antigen by only a single amino acid, with attendant implications for therapeutic development.

scholarly journals High Consistency of Structure-Based Design and X-Ray Crystallography: Design, Synthesis, Kinetic Evaluation and Crystallographic Binding Mode Determination of Biphenyl-N-Acyl-β-D-Glucopyranosylamines as Glycogen Phosphorylase Inhibitors

2019 ◽  
Author(s):  
Thomas Fischer ◽  
Symeon M. Koulas ◽  
Anastasia S. Tsagkarakou ◽  
Efthimios Kyriakis ◽  
George A. Stravodimos ◽  
...  
Keyword(s):  
Glycogen Phosphorylase ◽  
Catalytic Mechanism ◽  
Liver Glycogen ◽  
Binding Mode ◽  
Structural Water ◽  
Design Synthesis ◽  
Kinetic Evaluation ◽  
X Ray ◽  
X Ray Crystallography ◽  
Design And Synthesis

Structure-based design and synthesis of two biphenyl-N-acyl-β-D-glucopyranosylamine derivatives as well as their assessment as inhibitors of human liver glycogen phosphorylase (hlGPa, a pharmaceutical target for type 2 diabetes) is presented. X-ray crystallography revealed the importance of structural water molecules and that the inhibitory efficacy correlates with the degree of disturbance caused by the inhibitor binding to a loop crucial for the catalytic mechanism. The in silico derived models of the binding mode generated during the design process corresponded very well with the crystallographic data.

Structure-Based Design, Synthesis, and X-ray Crystallography of a High-Affinity Antagonist of the Grb2-SH2 Domain Containing an Asparagine Mimetic

1999 ◽  
Vol 42 (13) ◽  
pp. 2358-2363 ◽  
Author(s):  
Pascal Furet ◽  
Carlos García-Echeverría ◽  
Brigitte Gay ◽  
Joseph Schoepfer ◽  
Martin Zeller ◽  
...  
Keyword(s):  
Sh2 Domain ◽  
Design Synthesis ◽  
X Ray ◽  
X Ray Crystallography ◽  
High Affinity

scholarly journals Highly potent macrocyclic BACE-1 inhibitors incorporating a hydroxyethylamine core: Design, synthesis and X-ray crystal structures of enzyme inhibitor complexes

2012 ◽  
Vol 20 (14) ◽  
pp. 4377-4389 ◽  
Author(s):  
Veronica Sandgren ◽  
Tatiana Agback ◽  
Per-Ola Johansson ◽  
Jimmy Lindberg ◽  
Ingemar Kvarnström ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Enzyme Inhibitor ◽  
Design Synthesis ◽  
X Ray ◽  
Bace 1

De Novo Design, Synthesis, and X-ray Crystal Structures of Pyrrolinone-Based .beta.-Strand Peptidomimetics

1994 ◽  
Vol 116 (22) ◽  
pp. 9947-9962 ◽  
Author(s):  
Amos B. Smith ◽  
Mark C. Guzman ◽  
Paul A. Sprengeler ◽  
Terence P. Keenan ◽  
Ryan C. Holcomb ◽  
...  
Keyword(s):  
Crystal Structures ◽  
De Novo ◽  
De Novo Design ◽  
Design Synthesis ◽  
Beta Strand ◽  
X Ray
Sign in / Sign up

Export Citation Format

Share Document