The crystal structure of thymidylate synthase from Pneumocystis carinii reveals a fungal insert important for drug design

2000 ◽  
Vol 297 (3) ◽  
pp. 645-657 ◽  
Author(s):  
Amy C Anderson ◽  
Kathy M Perry ◽  
Douglas M Freymann ◽  
Robert M Stroud
Keyword(s):  
Crystal Structure ◽  
Drug Design ◽  
Thymidylate Synthase ◽  
Pneumocystis Carinii

Design, Synthesis, and X-ray Crystal Structure of a Potent Dual Inhibitor of Thymidylate Synthase and Dihydrofolate Reductase as an Antitumor Agent1

2000 ◽  
Vol 43 (21) ◽  
pp. 3837-3851 ◽  
Author(s):  
Aleem Gangjee ◽  
Jianming Yu ◽  
John J. McGuire ◽  
Vivian Cody ◽  
Nikolai Galitsky ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Dihydrofolate Reductase ◽  
Thymidylate Synthase ◽  
Dual Inhibitor ◽  
Design Synthesis ◽  
X Ray

scholarly journals Crystal structure of SARS-CoV-2 nsp10/nsp16 2′-O-methylase and its implication on antiviral drug design

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Sheng Lin ◽  
Hua Chen ◽  
Fei Ye ◽  
Zimin Chen ◽  
Fanli Yang ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Drug Design ◽  
Antiviral Drug

Structure-Based Drug Design of c-Kit Inhibitors for Use in the Treatment of Acute Myeloid Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1906-1906
Author(s):  
David S. Maxwell ◽  
Ashutosh Pal ◽  
Zhenghong Peng ◽  
Alexandr Shavrin ◽  
Stefan Faderl ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Acute Myeloid Leukemia ◽  
Drug Design ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Assay ◽  
Structure Based Drug Design ◽  
Acute Myeloid

Abstract Inhibitors of c-Kit kinase have shown clinical relevance in various myeloid disorders, including acute myeloid leukemia (AML). Research in our lab has been oriented towards structure-based drug design of c-Kit inhibitors based on the available crystal structure. We describe the design, synthesis, and preliminary results from the in-vitro testing of several c-Kit kinase inhibitors in both enzymatic and cell-based assays. The design resulted from in-silico screening of several targeted libraries via docking to the crystal structure of c-Kit, followed by aggressive post-filtering by several criteria to significantly bias synthesis efforts towards candidate compounds with best chance for success. This led to 128 structures built from 8 common structural cores, from which 2 cores were initially selected based on the synthetic feasibility. Five compounds were initially synthesized, and were immediately followed by 60 compounds with variations to probe local structure-activity relationships. The initial set of compounds, designated APCKxxx, was tested in a c-Kit kinase assay; two compounds were found to have an IC50 in the high nM to low uM range. These compounds have been tested in a MTT-based assay using OCIM2 and OCI/AML3 cell lines. In the c-Kit expressing OCI/AML3 cell line, all five compounds possessed an EC50 < 500 nM and two had and EC50 ~100 nM. Our most recent results show that these compounds also show efficacy in some imatinib-resistant cell lines. We will discuss these results and our strategies for the second generation of compounds that are optimized for better activity, selectivity, and ADME properties.

Crystal-structure-based design and synthesis of benz[cd]indole-containing inhibitors of thymidylate synthase

1992 ◽  
Vol 35 (4) ◽  
pp. 663-676 ◽  
Author(s):  
Michael D. Varney ◽  
Gifford P. Marzoni ◽  
Cindy L. Palmer ◽  
Judith G. Deal ◽  
Stephanie Webber ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Thymidylate Synthase ◽  
Design And Synthesis

scholarly journals The crystal structure of alanine racemase from Streptococcus pneumoniae, a target for structure-based drug design

2011 ◽  
Vol 11 (1) ◽  
pp. 116 ◽  
Author(s):  
Hookang Im ◽  
Miriam L Sharpe ◽  
Ulrich Strych ◽  
Milya Davlieva ◽  
Kurt L Krause
Keyword(s):  
Crystal Structure ◽  
Streptococcus Pneumoniae ◽  
Drug Design ◽  
Alanine Racemase ◽  
Structure Based Drug Design

scholarly journals Crystal structure of pyrimidine-nucleoside phosphorylase fromBacillus subtilisin complex with imidazole and sulfate

2018 ◽  
Vol 74 (4) ◽  
pp. 193-197 ◽  
Author(s):  
V. V. Balaev ◽  
I. I. Prokofev ◽  
A. G. Gabdoulkhakov ◽  
C. Betzel ◽  
A. A. Lashkov
Keyword(s):  
Crystal Structure ◽  
Bacillus Subtilis ◽  
Drug Design ◽  
Binding Site ◽  
Anticancer Drug ◽  
Imidazole Ring ◽  
Pyrimidine Nucleoside ◽  
Nucleoside Phosphorylase ◽  
Pyrimidine Nucleoside Phosphorylase

Pyrimidine-nucleoside phosphorylase catalyzes the phosphorolytic cleavage of thymidine and uridine with equal activity. Investigation of this protein is essential for anticancer drug design. Here, the structure of this protein fromBacillus subtilisin complex with imidazole and sulfate is reported at 1.9 Å resolution, which is an improvement on the previously reported structure at 2.6 Å resolution. The localization and position of imidazole in the nucleoside-binding site reflects the possible binding of ligands that possess an imidazole ring.

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