2C2S
Human Dihydrofolate Reductase Complexed With NADPH and 2,4-Diamino-5-(1-o-carboranylmethyl)-6-methylpyrimidine, A novel boron containing, nonclassical Antifolate
Summary for 2C2S
| Entry DOI | 10.2210/pdb2c2s/pdb |
| Related | 1BOZ 1DHF 1DLR 1DLS 1DRF 1HFP 1HFQ 1HFR 1KMS 1KMV 1MVS 1MVT 1OHJ 1OHK 1PD8 1PD9 1PDB 1S3U 1S3V 1S3W 1U71 1U72 2C2T 2DHF |
| Descriptor | DIHYDROFOLATE REDUCTASE, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 2,4-DIAMINO-5-(1-O-CARBORANYLMETHYL)-6-METHYLPYRIMIDINE, ... (5 entities in total) |
| Functional Keywords | nonclassical antifolates, lipophilic antifolates, nadp, one- carbon metabolism, oxidoreductase, reductase |
| Biological source | HOMO SAPIENS (HUMAN) |
| Total number of polymer chains | 2 |
| Total formula weight | 44842.75 |
| Authors | Leung, A.K.W.,Reynolds, R.C.,Riordan, J.M.,Borhani, D.W. (deposition date: 2005-09-29, release date: 2007-04-10, Last modification date: 2024-05-01) |
| Primary citation | Reynolds, R.C.,Campbell, S.R.,Fairchild, R.G.,Kisliuk, R.L.,Micca, P.L.,Queener, S.F.,Riordan, J.M.,Sedwick, W.D.,Waud, W.R.,Leung, A.K.W.,Dixon, R.W.,Suling, W.J.,Borhani, D.W. Novel Boron-Containing, Nonclassical Antifolates: Synthesis and Preliminary Biological and Structural Evaluation. J.Med.Chem., 50:3283-, 2007 Cited by PubMed Abstract: Two boron-containing, ortho-icosahedral carborane lipophilic antifolates were synthesized, and the crystal structures of their ternary complexes with human dihydrofolate reductase (DHFR) and dihydronicotinamide adenine dinucleotide phosphate were determined. The compounds were screened for activity against DHFR from six sources (human, rat liver, Pneumocystis carinii, Toxoplasma gondii, Mycobacterium avium, and Lactobacillus casei) and showed good to modest activity against these enzymes. The compounds were also tested for antibacterial activity against L. casei, M. tuberculosis H37Ra, and three M. avium strains and for cytotoxic activity against seven different human tumor cell lines. Antibacterial and cytotoxic activity was modest, with one sample, the closo-carborane 4, showing about 10-fold greater activity. The less toxic nido-carborane 2 was also tested as a candidate for boron neutron capture therapy, but showed poor tumor retention and low selectivity ratios for boron distribution in tumor tissue versus normal tissue. PubMed: 17569517DOI: 10.1021/JM0701977 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.4 Å) |
Structure validation
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