Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.5.1.3 (dihydrofolate reductase)
 5,819 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent evidences suggest that cancer treatment based on combination of cytostatic and conventional chemostatic therapeutics, which are usually cytotoxic, can provide an improved curative option. On the sequence of our previous work on methotrexate (MTX) derivatives, we have developed and evaluated novel MTX analogues, containing a pteridine moiety conjugated with benzenesulfonamide derivatives, thus endowed with the potential capacity for dual inhibition of dihydrofolate reductase (DHFR) and carbonic anhydrases (CA). These enzymes are often overexpressed in tumors and are involved in two unrelated cellular pathways, important for tumor survival and progression. Their simultaneous inhibition may turn beneficial in terms of enhanced antitumor activity. Herein we report the design and synthesis of several diaminopteridine-benzenesulfonamide and -benzenesulfonate conjugates, differing in the nature and size of the spacer group between the two key moieties. The inhibition studies performed on a set of CAs and DHFR, revealed the activities in the low nanomolar and low micromolar ranges of concentration, respectively. Some inhibitors showed selectivity for the tumor-related CA (isozyme IX). Cell proliferation assays using two tumor cell lines (the non-small cell lung carcinoma, A549, and prostate carcinoma, PC-3) showed activities only in the millimolar range. Nevertheless, this fact points out the need of improving the cell intake properties of these new compounds, since the general inhibitory profiles revealed their potential as anticancer agents.
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PMID:Pteridine-sulfonamide conjugates as dual inhibitors of carbonic anhydrases and dihydrofolate reductase with potential antitumor activity. 2058 May 61

Both DHPS (dihydropteroate synthase) and DHFR (dihydrofolate reductase) play important physiological roles in the survivability of Mycobacterium tuberculosis (MTB). Sulfonamides are the potent drugs to monitor growth and proliferation of MTBs by inhibiting the activity of DHPS and DHFR which could explain the mechanism of action of these molecules. In this work, 102 heterocyclic sulfonamides (HSF) have been screened by discovery studio molecular docking programme to search the best suitable molecule for the treatment of MTBs. Lipinski's rule of five protocols is followed to screen drug likeness of these molecules and ADMET (absorption, distribution, metabolism, excretion and toxicity) filtration has been used to value their toxicity. Only fourteen molecules are found to obey the Lipinski's rule and able to cross the ADMET filter. A small difference between HOMO and LUMO energy signifies the electronic excitation energy which is essential to calculate molecular reactivity and stability of the best docked compound and easy activation of drug in the protein environment. Both 4-amino-N-(6-hydroxypyridin-2-yl)benzenesulfonamide (M1) and 4-amino-N-(9H-carbazol-2-yl)benzenesulfonamide (M2) show the best theoretical efficiency with DHPS and DHFR, respectively. These compounds are also found to bind to the adenine-thymine region of tuberculosis DNA.
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PMID:Sulfonamide derivatives as Mycobacterium tuberculosis inhibitors: in silico approach. 3060 17