Covalent drug binding

Tracy, J. W., Catto, B. A. and Webster, L. T., Jr (1983) Reductive metaboism of niridazole by Schistosoma mansoni correlation with covalent drug binding to parasite macromolecules. Mol. Pharmacol. 24 291-299. 

Fig. 2.26 Plot of the DBQ (Drug, D)/CMVP A144L (Protein, P) molar ratios for the incubated concentrations as a function of the non-covalently bound concentrations as determined in the titration study of the GPC spin column eluates assayed by ESI-MS (see Table 2.5). The shape of the curve indicates that up to three drugs bind non-covalently and non-specifically to CMVP A144L.

In the absence of 02, there is little if any strand breakage instead the drug binds covalently to DNA (Povirk and Goldberg 1982, 1984) and induces, under certain conditions, interstrand DNA cross-links (Xu et al. 1997) with the same base specificity as SSB formation in the presence of 02 (Povirk and Goldberg 1985a). 

Dong JQ, Smith PC. Glucuronidation and covalent protein binding of benoxapro-fen and flunoxaprofen in sandwich-cultured rat and human hepatocytes. Drug Metab Dispos. 2009 37(12) 2314-2322. 

Rifampicin (Fig. 10.70) is a semisynthetic rifamycin made from rifamycin B—an antibiotic isolated from Streptomyces mediterranei. It inhibits Gram-positive bacteria and works by binding non-covalently to RNA polymerase and inhibiting RNA synthesis. The DNA-dependent RNA polymerases in eukaryotic cells are unaffected, since the drug binds to a peptide chain not present in the mammalian RNA polymerase. It is therefore highly selective. 

Loo.T.W., Bartlett, M.C.. and Clarke, D.M. (2003) Permanent activation of the human P-glycoprotein by covalent modification of a residue in the drug-binding site. The Journal of Biological Chemistry. 278, 20449-20452. 

An important early observation was that cis-DDP, the antitumor drug, binds covalently and not by intercalation to DNA (l 5) We present evidence to support this conclusion later in the section describing the effects of ethidium bromide on platinum binding. Since platinum(ll), when bound to nitrogen ligands, is rather inert kinetically (16), platinum-DNA adducts may be isolated and studied without appreciable platinum loss. 

Drug-receptor bonds Drugs bind to receptors with a variety of chemical bonds. These include very strong covalent bonds (which usually result in irreversible action), somewhat weaker electrostatic bonds (eg, between a cation and an anion), and much weaker interactions (eg, hydrogen, van der Waals, and hydrophobic bonds). 

Ortiz de Montellano PR (2008) Mechanism and role of covalent heme binding in CYP4 family P450 enzymes and mammalian peroxidases. Drug Metab Rev 40 405 26... 

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