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Computer-aided identification of ochratoxin antagonists
Angelo Vedani and D.R. Mc Master
Biographics Laboratory 3R, 4055 Basel, Switzerland.
Keywords: drug-design; pharmacology; qsar; in silico; reduction; toxicity testing: pharmaceuticals; toxicity testing: xenobiotics
Duration: 2 years Project Completion: 1999
Background and Aim
This project aims at to discover an antidote for ochratoxin A (OcA), a mycotoxin released by moulds growing on grains, peanuts and vegetables. In animals, ochratoxin is nephrotoxic, genotoxic, teratogenic, carcinogenic and immunosuppressive. The compound has been linked to Balkan Endemic Nephropathy, a kidney disease frequently observed in the Balkan countries. The toxicity of OcA is thought to be due primarily to the inhibition of phenylalanine-tRNA synthetase (PheRS).
Method and Results
Simulating the molecular-dynamic behaviour of PheRS-OcA in aqueous solution, we have identified three quite different binding modes between the toxin and the enzyme, all of which suggest an affinity only in the millimolar range. This contradicts older toxicological findings, but is in agreement with more recent in vitro studies. In vivo, OcA binds preferentially to serum albumin, a plasma protein, with a corresponding effect on the toxicokinetics of the mycotoxin including a delay of the excretion rate. Antagonizing this effect under chronic low exposure to OcA might lead to the immediate elimination of the toxin by excretion and might prevent the accumulation of the mycotoxin in the body. Based on the three-dimensional structure of human serum albumin, we have simulated its interaction with OcA. The long-term goal of our study is to identify a synthetic antagonist with an affinity towards albumin between that of OcA and the endogenous ligands.
Conclusions and Relevance for 3R
Using computational technologies, we demonstrated that i) phenylalanine-tRNA synthetase is of questionable relevance in OcA action and ii) that its adverse effects may possibly all be eliminated by the design of a synthetic antagonist binding appropriately to serum albumin. Such computer-aided investigations of the structure-binding properties help to reduce the number of animal tests necessary to assess the toxicity of a given chemical.
updated version 2007 (pdf file)
MacMasters, D.R. und Vedani, A. (1998). Ochratoxine: Molekulare Strategien zur Entwicklung eines Gegengiftes. ALTEX 15, 218-221.
MacMasters, D.R. und Vedani, A. (1999). Ochratoxin A binding to phenylalanyl-tRNA synthetase: A computational approach to ochratoxicosis and its antagonism, J.Med.Chem. 42(16):3075-86.