Ligand-protein docking has been developed and used in facilitating new drug discoveries. In this approach, docking single or multiple small molecules to a receptor site is attempted to find putative ligands. A number of studies have shown that docking algorithms are capable of finding ligands and binding conformations at a receptor site close to experimentally determined structures. These algorithms are expected to be equally applicable to the identification of multiple proteins to which a small molecule can bind or weakly bind. We introduce a ligand-protein inverse-docking approach for finding potential protein targets of a small molecule by the computer-automated docking search of a protein cavity database. This database is developed from protein structures in the Protein Data Bank (PDB). Docking is conducted with a procedure involving multiple-conformer shape-matching alignment of a molecule to a cavity followed by molecular-mechanics torsion optimization and energy minimization on both the molecule and the protein residues at the binding region. Scoring is conducted by the evaluation of molecular-mechanics energy and, when applicable, by the further analysis of binding competitiveness against other ligands that bind to the same receptor site in at least one PDB entry. Testing results on two therapeutic agents, 4H-tamoxifen and vitamin E, showed that 50% of the computer-identified potential protein targets were implicated or confirmed by experiments. The application of this approach may facilitate the prediction of unknown and secondary therapeutic target proteins and those related to the side effects and toxicity of a drug or drug candidate. Proteins 2001;43:217-226.

Ligand-protein inverse docking and its potential use in the computer search of protein targets of a small molecule.

Measurement of erythrocyte lipids, lipid peroxidation, antioxidants and osmotic fragility in cervical cancer patients.

Relations among aging, antioxidant status, and cataract

Experimental evidence suggests that oxidative stress due to the accumulation of free radicals plays a role in the pathogenesis of cataracts and that the process can be prevented or ameliorated by antioxidants. In addition, a recent study found that cataract patients tended to have lower serum levels of vitamins C, E, or carotenoids than did control subjects. This investigation, which compared the self-reported consumption of supplementary vitamins by 175 cataract patients with that of 175 individually matched, cataract-free subjects, revealed that the latter group used significantly more supplementary vitamins C and E (p = 0.01 and 0.004, respectively). Inasmuch as the observed reduction in risk of cataracts was at least 50%, a randomized, controlled trial of vitamin supplementation in cataract prevention seems justified.

Vitamin E intake and risk of cataracts in humans.

Antioxidant profile in the circulation of patients with fibroadenoma and adenocarcinoma of the breast

High doses of orally administered vitamin E (1000 IU/day) have been given to ten normal volunteers. Ten control subjects received placebo. Red blood cell glutathione was significantly higher in treated subjects than in the controls (controls: 267.5 +/- 15.7 micrograms/mL; treated: 374.8 +/- 17.3 micrograms/mL). These findings could be explained by an increase of glutathione synthesis brought about by the stimulation of glutathione synthetase activity. An alternative possibility is a reduced utilization of glutathione for the detoxification of free radicals. These two mechanisms could be effective in counteracting the glutathione content feedback of the synthetizing enzymes.

Vitamin E and red blood cell glutathione

In vitro effect of alpha-tocopherol on lysophosphatidylcholine-induced lens damage.

We tried to counteract the appearance of galactosemic cataracts in weaned rats by high doses of vitamin E. Rats were fed a diet containing 33% galactose. Cataract development was monitored by biomicro

Changes of Some Biochemical Parameters of the Lens in Galactose-Treated Weaned Rats with and without Vitamin E Therapy

Since many years experimental evidences have suggested an association between nutrition and lens opacities. A dietary deficiency of antioxidants and reactive oxygen scavengers may be involved in the pathogenesis of the "idiopathic" human senile cataract, as it has been demonstrated in some experimental cataracts. We tested the levels of ascorbic acid (vit. C), alpha-tocopherol (vit. E), reduced glutathione (GSH) and malondialdehyde (MDA) in the plasma or in the red blood cells (RBC) of 42 patients who were affected by surgically significant cataract and of 40 age-matched controls. Plasma vit. C mean level was 4.46 gamma/ml in cataracts and 4.62 gamma/ml in controls, while vit. E level was 7.70 and 7.09 gamma/ml respectively. RBC GSH was found to be 342 gamma/ml in cataracts and 346 in controls, while the MDA content was 4.06 picoMol/ml and 4.08 picoMol/ml respectively. The level of each tested nutrient or metabolite was not found to be statistically different between cataractous patients and controls, nor any significant trend was found to be present when the nutrients and metabolites were correlated to each other. Our results do not support the hypothesis of a nutritional deficiency in human senile cataracts. However, a defect in the antioxidative metabolism pathways could be present either systemically or at lens level.

Cataract risk factors: blood level of antioxidative vitamins, reduced glutathione and malondialdehyde in cataractous patients.

Serum free and total tryptophan levels have been measured in patients with cataracts and compared with the same levels in controls with clear lenses. No statistically significant differences have been demonstrated between the two groups of examined fasting subjects. Preliminary results seem to indicate that differences could be evident after L-tryptophan oral load.

T Libondi

Papers

Vitamin E and red blood cell glutathione

In vitro effect of alpha-tocopherol on lysophosphatidylcholine-induced lens damage.

Changes of Some Biochemical Parameters of the Lens in Galactose-Treated Weaned Rats with and without Vitamin E Therapy

Cataract risk factors: blood level of antioxidative vitamins, reduced glutathione and malondialdehyde in cataractous patients.

Serum tryptophan in humans with senile cataracts.