Rational Design of a Low Molecular Weight, Stable, Potent, and Long-Lasting GPR103 Aza-β3-pseudopeptide Agonist

2012 ◽  
Vol 55 (17) ◽  
pp. 7516-7524 ◽  
Author(s):  
Cindy Neveu ◽  
Benjamin Lefranc ◽  
Olivier Tasseau ◽  
Jean-Claude Do-Rego ◽  
Adèle Bourmaud ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Rational Design ◽  
Low Molecular Weight

scholarly journals Structure–activity Relationships of Glutathione Peroxidase 4 Inhibitor Warheads

2020 ◽  
Author(s):  
John Eaton ◽  
Laura Furst ◽  
Luke Cai ◽  
Vasanthi S. Viswanathan ◽  
Stuart L. Schreiber
Keyword(s):  
Molecular Weight ◽  
Glutathione Peroxidase ◽  
Active Site ◽  
Rational Design ◽  
Covalent Modification ◽  
Low Molecular Weight ◽  
Phenotypic Screening ◽  
Direct Inhibition ◽  
Systematic Assessment ◽  
Structure Activity

<p>Direct inhibition of GPX4 requires covalent modification of the active-site selenocysteine. While phenotypic screening has revealed that activated alkyl chlorides and masked nitrile-oxides can inhibit GPX4 covalently, a systematic assessment of potential electrophilic warheads with the capacity to inhibit cellular GPX4 has been lacking. Here we survey more than 25 electrophilic warheads across several distinct GPX4-targeting scaffolds. Surprisingly, we find that electrophiles with attenuated reactivity compared to chloroacetamides are unable to target GPX4. The highly reactive propiolamide warheads we uncover in this study highlight the potential need for masking strategies similar to those we have described for nitrile-oxide-based GPX4 inhibitors. Finally, our observations that there are spatial requirements between warhead and scaffold for achieving optimal GPX4 targeting and that certain low-molecular-weight analogs inhibit GPX4 with selectivity suggest that rational design of GPX4 inhibitors may be a productive approach. The generation of ligand-bound crystal structures to facilitate such studies should therefore be prioritized by the field. </p>

scholarly journals Rational design of low-molecular weight heparins with improved in vivo activity

2003 ◽  
Vol 100 (2) ◽  
pp. 651-656 ◽  
Author(s):  
M. Sundaram ◽  
Y. Qi ◽  
Z. Shriver ◽  
D. Liu ◽  
G. Zhao ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Rational Design ◽  
Low Molecular Weight ◽  
Low Molecular Weight Heparins

Screening and Rational Design of Low Molecular Weight HIV Fusion Inhibitors

2010 ◽  
Vol 86 (1) ◽  
pp. A55
Author(s):  
Miriam Gochin ◽  
Guangyan Zhou ◽  
Dong Wu ◽  
Landon Whitby ◽  
Dale Boger ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Rational Design ◽  
Low Molecular Weight ◽  
Fusion Inhibitors

scholarly journals Small molecule-mediated co-assembly of amyloid-β oligomers reduces neurotoxicity through promoting non-fibrillar aggregation

2020 ◽  
Vol 11 (27) ◽  
pp. 7158-7169 ◽  
Author(s):  
Hao Liu ◽  
Chengyuan Qian ◽  
Tao Yang ◽  
Yanqing Wang ◽  
Jian Luo ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Blood Brain Barrier ◽  
Small Molecule ◽  
Rational Design ◽  
Amyloid Β ◽  
Low Molecular Weight ◽  
Aβ Oligomers ◽  
Barrier Permeability ◽  
Blood Brain Barrier Permeability ◽  
Brain Barrier Permeability

A rational design of pincer-like scaffold-based small molecule with blood-brain barrier permeability that can specifically co-assemble with low molecular weight Aβ oligomers to form non-fibrillar, degradable, non-toxic co-aggregates.

Low molecular weight self-assembling peptide-based materials for cell culture, antimicrobial, anti-inflammatory, wound healing, anticancer, drug delivery, bioimaging and 3D bioprinting applications

Soft Matter ◽  
2020 ◽  
Vol 16 (44) ◽  
pp. 10065-10095
Author(s):  
Apurba K. Das ◽  
Pramod K. Gavel
Keyword(s):  
Drug Delivery ◽  
Molecular Weight ◽  
Cell Culture ◽  
Wound Healing ◽  
Rational Design ◽  
Low Molecular Weight ◽  
3D Bioprinting ◽  
Anticancer Drug Delivery ◽  
Self Assembling ◽  
Anti Inflammatory

This article emphasizes on the rational design and development of self-assembling peptide-based materials for cell culture, antimicrobial, anti-inflammatory, anticancer, wound healing, drug delivery, bioimaging and 3D bioprinting applications.

scholarly journals Structure–activity Relationships of Glutathione Peroxidase 4 Inhibitor Warheads

2020 ◽  
Author(s):  
John Eaton ◽  
Laura Furst ◽  
Luke Cai ◽  
Vasanthi S. Viswanathan ◽  
Stuart L. Schreiber
Keyword(s):  
Molecular Weight ◽  
Glutathione Peroxidase ◽  
Active Site ◽  
Rational Design ◽  
Covalent Modification ◽  
Low Molecular Weight ◽  
Phenotypic Screening ◽  
Direct Inhibition ◽  
Systematic Assessment ◽  
Structure Activity

<p>Direct inhibition of GPX4 requires covalent modification of the active-site selenocysteine. While phenotypic screening has revealed that activated alkyl chlorides and masked nitrile-oxides can inhibit GPX4 covalently, a systematic assessment of potential electrophilic warheads with the capacity to inhibit cellular GPX4 has been lacking. Here we survey more than 25 electrophilic warheads across several distinct GPX4-targeting scaffolds. Surprisingly, we find that electrophiles with attenuated reactivity compared to chloroacetamides are unable to target GPX4. The highly reactive propiolamide warheads we uncover in this study highlight the potential need for masking strategies similar to those we have described for nitrile-oxide-based GPX4 inhibitors. Finally, our observations that there are spatial requirements between warhead and scaffold for achieving optimal GPX4 targeting and that certain low-molecular-weight analogs inhibit GPX4 with selectivity suggest that rational design of GPX4 inhibitors may be a productive approach. The generation of ligand-bound crystal structures to facilitate such studies should therefore be prioritized by the field. </p>

Rational design of protein–protein interaction inhibitors

MedChemComm ◽  
2015 ◽  
Vol 6 (1) ◽  
pp. 51-60 ◽  
Author(s):  
Didier Rognan
Keyword(s):  
Molecular Weight ◽  
Tumor Suppressor ◽  
Protein Interaction ◽  
Rational Design ◽  
Low Molecular Weight ◽  
P53 Tumor Suppressor ◽  
Protein Protein Interaction

Low molecular weight compound competing for the binding of the p53 tumor suppressor to the MDM2 oncoprotein.

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