2C2S

Human Dihydrofolate Reductase Complexed With NADPH and 2,4-Diamino-5-(1-o-carboranylmethyl)-6-methylpyrimidine, A novel boron containing, nonclassical Antifolate

2C2S の概要

• エントリーDOI: 10.2210/pdb2c2s/pdb
• 関連するPDBエントリー: 1BOZ 1DHF 1DLR 1DLS 1DRF 1HFP 1HFQ 1HFR 1KMS 1KMV 1MVS 1MVT 1OHJ 1OHK 1PD8 1PD9 1PDB 1S3U 1S3V 1S3W 1U71 1U72 2C2T 2DHF
• 分子名称: DIHYDROFOLATE REDUCTASE, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 2,4-DIAMINO-5-(1-O-CARBORANYLMETHYL)-6-METHYLPYRIMIDINE, ... (5 entities in total)
• 機能のキーワード: nonclassical antifolates, lipophilic antifolates, nadp, one- carbon metabolism, oxidoreductase, reductase
• 由来する生物種: HOMO SAPIENS (HUMAN)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 44842.75

構造登録者

Leung, A.K.W.,Reynolds, R.C.,Riordan, J.M.,Borhani, D.W. (登録日: 2005-09-29, 公開日: 2007-04-10, 最終更新日: 2024-05-01)

主引用文献

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

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: 17569517
DOI: 10.1021/JM0701977

実験手法

X-RAY DIFFRACTION (1.4 Å)