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《Bioorganic & medicinal chemistry letters》2020,30(16):127292
Effective therapies are lacking to treat gastrointestinal infections caused by the genus Cryptosporidium, which can be fatal in the immunocompromised. One target of interest is Cryptosporidium hominis (C. hominis) thymidylate synthase-dihydrofolate reductase (ChTS-DHFR), a bifunctional enzyme necessary for DNA biosynthesis. Targeting the TS-TS dimer interface is a novel strategy previously used to identify inhibitors against the related bifunctional enzyme in Toxoplasma gondii. In the present study, we target the ChTS dimer interface through homology modeling and high-throughput virtual screening to identifying allosteric, ChTS-specific inhibitors. Our work led to the discovery of methylenedioxyphenyl-aminophenoxypropanol analogues which inhibit ChTS activity in a manner that is both dose-dependent and influenced by the conformation of the enzyme. Preliminary results presented here include an analysis of structure activity relationships and a ChTS-apo crystal structure of ChTS-DHFR supporting the continued development of inhibitors that stabilize a novel pocket formed in the open conformation of ChTS-TS. 相似文献
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Mahamadhanif S. Shaikh Ashish M. Kanhed Balakumar Chandrasekaran Mahesh B. Palkar Nikhil Agrawal Christian Lherbet Girish A. Hampannavar Rajshekhar Karpoormath 《Bioorganic & medicinal chemistry letters》2019,29(16):2338-2344
InhA (Enoyl-ACP reductase) plays a crucial role in the biosynthetic pathway of cell wall synthesis in Mycobacterium tuberculosis (Mtb). Isoniazid (INH) is an important first-line drug, which inhibits InhA. The rapid increase in resistance to INH and currently marketed drugs as well as emergence of MDR-TB and XDR-TB has complicated the diagnosis and treatment of Mtb with ever increasing threat to human kind. Herein, we report novel N-methyl carbazole derivatives as potential anti-TB compounds acting directly via InhA inhibition. All the synthesized final compounds were screened against Mtb virulent cell line H37Rv and investigated the InhA enzyme inhibition. Interestingly, compound 9e displayed promising inhibition (91%) at 50 µM concentration and IC50 of 2.82 µM against InhA. To understand the ligand receptor interaction between compound 9e and InhA, molecular docking and molecular dynamics experiments were performed. The computational results were in agreement with the observed experimental data. Further, the cytotoxicity studies on mammalian cells revealed that all the compounds were safe. 相似文献
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Samukelisiwe Pretty Khathi Balakumar Chandrasekaran Sivanandhan Karunanidhi Chuin Lean Tham Frank Kozielski Nisar Sayyad Rajshekhar Karpoormath 《Bioorganic & medicinal chemistry letters》2018,28(17):2930-2938
A novel series of 1,3,4-thiadiazole-thiazolone hybrids 5a–v were designed, synthesized, characterized, and evaluated against the basal and the microtubule (MT)-stimulated ATPase activity of Eg5. From the evaluated derivatives, 5h displayed the highest inhibition with an IC50 value of 13.2?µM against the MT-stimulated Eg5 ATPase activity. Similarly, compounds 5f and 5i also presented encouraging inhibition with IC50 of 17.2?µM and 20.2?µM, respectively. A brief structure–activity relationship (SAR) analysis indicated that 2-chloro and 4-nitro substituents on the phenyl ring of the thiazolone motif contributed significantly to enzyme inhibition. An in silico molecular docking study using the crystal structure of Eg5 further supported the SAR and reasoned the importance of crucial molecular protein–ligand interactions in influencing the inhibition of the ATPase activity of Eg5. The magnitude of the electron-withdrawing functionalities over the hybrids and the critical molecular interactions contributed towards higher in vitro potency of the compounds. The drug-like properties of the synthesized compounds 5a–v were also calculated based on the Lipinski’s rule of five and in silico computation of key pharmacokinetic parameters (ADME). Thus, the present work unveils these hybrid molecules as novel Eg5 inhibitors with promising drug-like properties for future development. 相似文献
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Khunza Meraj Manoj Kumar Mahto N Blessy Christina Nidhi Desai Sajad Shahbazi Matcha Bhaskar 《Bioinformation》2012,8(23):1139-1146
The sodium “channelopathies” are the first among the ion channel diseases identified and have attracted widespread clinical and
scientific interests. Human voltage gated sodium channels are sites of action of several antiarrhythmic drugs, local anesthetics and
related antiepileptic drugs. The present study aims to optimize the activity of Disopyramide, by modification in its structures
which may improve the drug action by reducing its side effects. Herein, we have selected Human voltage-gated sodium channel
protein type 5 as a potent molecular target. Nearly eighty analogs of Disopyramide are designed and optimized. Thirty are selected
for energy minimization using Discovery studio and the LigPrep 2.5. Prior to docking, the active sites of all the proteins are
identified. The processing, optimization and minimization of all the proteins is done in Protein preparation wizard. The docking
study is performed using the GLIDE. Finally top five ranked lead molecules with better dock scores are identified as having strong
binding affinity to 2KAV protein than Disopyramide based on XP G scores. These five leads are further docked with other similar
voltage gated sodium channel proteins (PDB IDs: 2KBI, 4DCK, 2L53 and 4DJC) and the best scoring analog with each protein is
identified. Drug likeliness and comparative bioactivity analysis for all the analogs is done using QikProp 3.4. Results have shown
that the top five lead molecules would have the potential to act as better drugs as compared to Disopyramide and would be of
interest as promising starting point for designing compounds against various Sodium channelopathies. 相似文献
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