Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 

Saved Queries

Sign in to use this feature.

Search Filter Reset All

Years

Between: -

Subjects

remove_circle_outline
remove_circle_outline
Add Subjects Reset
Select Subjects

Journals

remove_circle_outline
Add Journals Reset
Select Journals

Article Types

remove_circle_outline
Add Article Types Reset
Select Article Types

Countries / Regions

remove_circle_outline
remove_circle_outline
Add Countries / Regions Reset
Select Countries / Regions
Update Search
share announcement

Search Results (3)

Search Parameters:
Keywords = acrylamide warhead

Order results
Result details
Results per page
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
25 pages, 6581 KiB  
Article
Identifying Ortholog Selective Fragment Molecules for Bacterial Glutaredoxins by NMR and Affinity Enhancement by Modification with an Acrylamide Warhead
by Ram B. Khattri, Daniel L. Morris, Stephanie M. Bilinovich, Erendra Manandhar, Kahlilah R. Napper, Jacob W. Sweet, David A. Modarelli and Thomas C. Leeper
Molecules 2020, 25(1), 147; https://doi.org/10.3390/molecules25010147 - 30 Dec 2019
Cited by 4 | Viewed by 5156
Abstract
Illustrated here is the development of a new class of antibiotic lead molecules targeted at Pseudomonas aeruginosa glutaredoxin (PaGRX). This lead was produced to (a) circumvent efflux-mediated resistance mechanisms via covalent inhibition while (b) taking advantage of species selectivity to target a fundamental [...] Read more.
Illustrated here is the development of a new class of antibiotic lead molecules targeted at Pseudomonas aeruginosa glutaredoxin (PaGRX). This lead was produced to (a) circumvent efflux-mediated resistance mechanisms via covalent inhibition while (b) taking advantage of species selectivity to target a fundamental metabolic pathway. This work involved four components: a novel workflow for generating protein specific fragment hits via independent nuclear magnetic resonance (NMR) measurements, NMR-based modeling of the target protein structure, NMR guided docking of hits, and synthetic modification of the fragment hit with a vinyl cysteine trap moiety, i.e., acrylamide warhead, to generate the chimeric lead. Reactivity of the top warhead-fragment lead suggests that the ortholog selectivity observed for a fragment hit can translate into a substantial kinetic advantage in the mature warhead lead, which bodes well for future work to identify potent, species specific drug molecules targeted against proteins heretofore deemed undruggable. Full article
(This article belongs to the Special Issue Fragment Based Drug Discovery)
►▼ Show Figures

Figure 1

16 pages, 3633 KiB  
Article
Design, Synthesis and Anti-Proliferative Activities of 2,6-Substituted Thieno[3,2-d]pyrimidine Derivatives Containing Electrophilic Warheads
by Qiumeng Zhang, Zonglong Hu, Qianqian Shen, Yi Chen and Wei Lu
Molecules 2017, 22(5), 788; https://doi.org/10.3390/molecules22050788 - 12 May 2017
Cited by 5 | Viewed by 6684
Abstract
Thieno[3,2-d]pyrimidine as an effective pharmacophore has been extensively studied. However, its 2,6-substituted derivatives are rarely reported. In the present study, eighteen 2,6-substituted thieno[3,2-d]pyrimidine derivatives containing electrophilic warheads were designed based on the first known Fibroblast growth factor receptor-4 (FGFR4) [...] Read more.
Thieno[3,2-d]pyrimidine as an effective pharmacophore has been extensively studied. However, its 2,6-substituted derivatives are rarely reported. In the present study, eighteen 2,6-substituted thieno[3,2-d]pyrimidine derivatives containing electrophilic warheads were designed based on the first known Fibroblast growth factor receptor-4 (FGFR4) inhibitor Blu9931. Unexpectedly, all of the derivatives exhibited negligible activity against FGFR4. However, most of the target compounds exhibited antiproliferative activities against four human cancer cell lines, including A431, NCI-H1975, Ramos and SNU-16. Compound 12 showed the most potent antiproliferative activities on the above four cell lines with IC50 values of 1.4 μM, 1.2 μM, 0.6 μM, and 2.6 μM, respectively. Additionally, the antiproliferative activity of 12 against MDA-MB-221 proved that 12 had the selectivity towards certain tumor cell lines. Furthermore, preliminary structure-activity relationship analysis was discussed based on the experimental data. Full article
(This article belongs to the Section Medicinal Chemistry)
►▼ Show Figures

Figure 1

23 pages, 9188 KiB  
Article
An NMR-Guided Screening Method for Selective Fragment Docking and Synthesis of a Warhead Inhibitor
by Ram B. Khattri, Daniel L. Morris, Caroline M. Davis, Stephanie M. Bilinovich, Andrew J. Caras, Matthew J. Panzner, Michael A. Debord and Thomas C. Leeper
Molecules 2016, 21(7), 846; https://doi.org/10.3390/molecules21070846 - 16 Jul 2016
Cited by 7 | Viewed by 8851
Abstract
Selective hits for the glutaredoxin ortholog of Brucella melitensis are determined using STD NMR and verified by trNOE and 15N-HSQC titration. The most promising hit, RK207, was docked into the target molecule using a scoring function to compare simulated poses to experimental [...] Read more.
Selective hits for the glutaredoxin ortholog of Brucella melitensis are determined using STD NMR and verified by trNOE and 15N-HSQC titration. The most promising hit, RK207, was docked into the target molecule using a scoring function to compare simulated poses to experimental data. After elucidating possible poses, the hit was further optimized into the lead compound by extension with an electrophilic acrylamide warhead. We believe that focusing on selectivity in this early stage of drug discovery will limit cross-reactivity that might occur with the human ortholog as the lead compound is optimized. Kinetics studies revealed that lead compound 5 modified with an ester group results in higher reactivity than an acrylamide control; however, after modification this compound shows little selectivity for bacterial protein versus the human ortholog. In contrast, hydrolysis of compound 5 to the acid form results in a decrease in the activity of the compound. Together these results suggest that more optimization is warranted for this simple chemical scaffold, and opens the door for discovery of drugs targeted against glutaredoxin proteins—a heretofore untapped reservoir for antibiotic agents. Full article
(This article belongs to the Special Issue Developments in Fragment-Based Lead Discovery)
►▼ Show Figures

Graphical abstract

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying article 1-50 on page 1 of 1.
Back to TopTop