Carbonic anhydrase inhibitors binding

ABSORPTION AND ELIMINATION The oral bioavadabrlity, plasma tj, and route of elimination of the three available carbonic anhydrase inhibitors are listed in Table 28-2. Carbonic anhydrase inhibitors bind avidly to the enzyme thus, tissues rich in this enzyme wdl have higher concentrations of drug following systemic administration. 

Taylor, P. W., and Burgen, A. S. V. Kinetics of carbonic anhydrase inhibitor complex formation. A comparison of anion- and sulfonamide-binding mechanisms. Biochemistry JO, 3859-3866(1971). 

Salicylates Interference with renal excretion of drugs that undergo active tubular secretion. Salicylate renal excretion dependent on urinary pH when large doses of salicylate used. Aspirin (but not other salicylates) interferes with platelet function. Large doses of salicylates have intrinsic hypoglycemic activity. Salicylates may displace drugs from plasma protein binding sites. Carbonic anhydrase inhibitors [NE] Increased acetazolamide serum concentrations increased salicylate toxicity due to decreased blood pH. 

Winum J-Y, Scozzafava A, Montero J-L, Supuran C-T (2008) Design of zinc binding functions for carbonic anhydrase inhibitors. Curr Pharm Des 14 615-621... 

Figure 15. Chemical structures of the carbonic anhydrase inhibitors 15-21. The small aromatic sulfonamides 15 and 16 bind with nanomolar affinity to carbonic anhydrase. Methazolamide 18 was used for a long time to treat glaucoma. 19 was the first topically active inhibitor. Structure-based drug design at Merck first led to 20 and then to the marketed drug, dorzolamide 21.

At Merck, the structure-based design of carbonic anhydrase inhibitors was started in the mid-1980s. The first compound with molecular modeling and X-ray structure determination playing an important role in the discovery process was thienothiopyrane-sulfonamide 20 (MK-927). This binds to carbonic anhydrase with a subnanomolar binding constant (Xi = 0.7 nM). 

Not fully established. One idea is that these carbonic anhydrase inhibitors (acetazolamide, diclofenamide) affect the plasma pH, so that more of the salicylate exists in the un-ionised (lipid-soluble) form, which can enter the CNS and other tissues more easily, leading to salicylate toxicity. However, carbonic anhydrase inhibitors also make the urine more alkaline, which increases the loss of salicylate (see also Aspirin or other Salicylates + Antacids , p.l35). Animal studies confirm that carbonic anhydrase inhibitors increase the lethal toxicity of aspirin. An alternative suggestion is that because salicylate inhibits the plasma protein binding of acetazolamide and its excretion by the kidney, acetazolamide toxicity, which mimics salicylate toxicity, may occur. ... 

Benzenesulfonamides, or more generally arylsulfonamides, are a class of carbonic anhydrase inhibitors that consist of a sulfonamide attached to an aromatic moiety, classically a benzyl ring [98-100]. The deprotonated sulfonamide coordinates the catalytically active Zn " in the substrate binding pocket of the enzyme (Figure 1.12). Many different additional substituents are tolerated on the aromatic system, as can be seen by the broad range of structures of carbonic anhydrase inhibitors in clinical use including dichlorophenamide, brinzolamide, and acetazolamide (Figure 1.13). 

Temperini, C. Innocenti, A. Scozzafava, A. Parkkila, S. Supuran, C.T. (2010). The Coumarin-binding site in carbonic anhydrase accommodates structurally diverse inhibitors The antiepileptic lacosamide as an example and lead molecule for novel classes of carbonic anhydrase inhibitors. Journal of Medicinal Chemistry, 53, 850-854. 

The buried Cys-212 of human carbonic anhydrase B (3 pM) is virtually unreactive towards 2-chloromercuric-4-nitrophenol (60 pM) at pH 9.2, but upon the addition of only 40 pM CN , the half-life drops to 10 minutes which is an, at least, 75-fold rate enhancement. On first analysis, this would suggest that inhibitor binding to the enzyme has produced a conformational change or altered the — SH environment of the Cys—212. This is unexpected. How would you prove by kinetic experiments that the CN is binding to the mercury compound and not the enzyme and that this is changing the reactivity. The rate reaches a constant value at high [CN ]. 

Generates structures similar to known inhibitors of HIV protease, FK506 binding protein and carbonic anhydrase... 

The idea of H2C03 as substrate for carbonic anhydrase is strongly supported by inhibitor binding studies158, 159. Small anion or sulfonamide inhibitors are linked to the zinc ion at high pH. The complex picks up a proton and the inhibitor is bound in a neutral form. 

Figure 7.6 ESI of zinc metalloenzyme carbonic anhydrase, (a)-(c) under acidic denaturing conditions (d)-(f) native state conditions and (g) native state conditions with a specific inhibitor. Structure of entry (d) is Protein Data Bank ID IBN1. Boriack-Sjodin, P.A., Zeitlin, S., Chen, H.H., Crenshaw, L, Gross S., Dantanarayana, A., Delgado, P., May J.A., Dean, T., Christianson, D.W. Structural analysis of inhibitor binding to human carbonic anhydrase II. Protein Sciv 1998, 7, 2483-2489.

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