Inhibitors specificity

The activity of P-lactamase inhibitors is often expressed as an IC q value, which is defined as the concentration of inhibitor that causes 50% inhibition of en2yme activity for a given set of conditions. IC q values, which vary widely according to substrate, time of incubation, and other factors, are presented herein solely to give an indication of potency and en2yme inhibitor specificity. Values that decrease with preincubation are indicative of irreversible inhibitors. 

Phenylmethanesulfonyl fluoride (PMSF) [329-98-6] M 174.2, m 90-91 , 92-93 . Purified by recrystn from ""CgHe, pet ether or CHCl3-pet ether. [Davies and Dick J Chem Soc 483 1932 cf Tullock and Coffman J Org Chem 23 2016 I 960.] It is a general protease inhibitor (specific for trypsin and chymotrypsin) and is a good substitute for diisopropylphosphoro floridate [Fahrney and Gould 7 Am Chem Soc 85 997 1963]. 

Anti-gout Drugs. Figure 1 Xanthine oxidase-catalyzed reactions. Xanthine oxidase converts hypoxanthine to xanthine and xanthine to uric acid, respectively. Hypoxanthine and xanthine are more soluble than uric acid. Xanthine oxidase also converts the uricostatic drug allopurinol to alloxanthine. Allopurinol and hypoxanthine are isomers that differ from each other in the substitution of positions 7 and 8 of the purine ring system. Although allopurinol is converted to alloxanthine by xanthine oxidase, allopurinol is also a xanthine oxidase inhibitor. Specifically, at low concentrations, allopurinol acts as a competitive inhibitor, and at high concentrations it acts as a noncompetitive inhibitor. Alloxanthine is a noncompetitive xanthine oxidase inhibitor. XOD xanthine oxidase. 

Cholinesterases (ChEs), polymorphic carboxyles-terases of broad substrate specificity, terminate neurotransmission at cholinergic synapses and neuromuscular junctions (NMJs). Being sensitive to inhibition by organophosphate (OP) poisons, ChEs belong to the serine hydrolases (B type). ChEs share 65% amino acid sequence homology and have similar molecular forms and active centre structures [1]. Substrate and inhibitor specificities classify ChEs into two subtypes ... 

An interesting feature of the influenza virus sialidase active site that offers the potential for developing inhibitors specific for N1 sialidases, including avian influenza A/H5N1 virus sialidase, has recently been revealed by X-ray crystallography. The... 

Kleim JP, ROsner M, Winkler I, Paessens A, Kirsch R, Hsiou Y, Arnolds E, Riess G (1996) Selective pressure of a quinoxaline nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) on HIV-1 replication results in the emergence of nucleoside RT-inhibitor-specific (RT Leu-74 -> Val or He and Val-75 - > Leu or He) HIV-1 mutants, Proc Natl Acad Sci USA 93 34-38... 

Oxidative desulfuration releases active sulfur that binds to, and deactivates, P450 Selective inhibitors Specific inhibitor of lAl Specific inhibitor of 1A2 Specific inhibitor of 2A6 Specific inhibitor of 2C9 Specific inhibitor of 2D1 Specific inhibitor of 2E1... 

DesJarlais RL, Seibel GL, Kuntz ID, Furth PS, Alvarez JC, Ortiz de Montellano PR, DeCamp DL, Babd LM, Craik CS. Structure-based design of nonpeptide inhibitors specific for the human immunodeficiency virus 1 protease. Proc Natl Acad Sci USA 1990 87 6644-8. 

Substrate/ligand/inhibitor specificity at optimized conditions... 

McKenna, M. C., Tildon, J. T., Stevenson, J. H. etal. Lactate transport by cortical synaptosomes from adult rat brain Characterization of kinetics and inhibitor specificity. Dev. Neurosci. 20 300-309,1998. 

Since the identification of hydroxamic acids as potent bidentate ZBGs, an enormous range of hydroxamic acid inhibitors based on this model has been developed and is described in numerous reviews and therefore will not be dealt with in depth here [17]. Instead, the focus of this report will be on efforts to improve on these "1st generation" inhibitors, specifically to improve biological and physicochemical characteristics, such as pharmacokinetics and bioavailability and to achieve isoform selectivity. 

Drugs known as integrase inhibitors and maturation inhibitors are also in development. Integrase inhibitors are designed to interfere with the integration of the viral genome while the maturation inhibitors specifically block the conversion of the HlV-1 capsid precursor, CA-SPl (p25) to mature capsid protein (p24). This blocking will result in defective core condensation and the release of noninfectious virus particles. 

Benzamides constitute a fourth dass of HDAC inhibitors. One example, MS-275, is a phenylenediamine derivative that exhibits robust HDAC inhibition in patients with advanced myeloid leukemia as well as refractory solid tumors or lymphoma in Phase I studies [72]. MS-275 is currently in Phase II trials. In a recent study aimed at optimizing the benzamide scaffold, several bis-(aryl) type analogs were synthesized and evaluated for their activity against a panel of HDACs [85]. Moradei et al. found that a thienyl substitution para to the free amino group in the phenylenediamine core rendered inhibitors specific for HDACsl, 2 with potency superior to that of MS-275. Isoform-specific inhibitors should aid in dissecting the roles of HDACs in normal cellular fundioning and cancer. 

Ji, H., Zhang, W., Zhang, M., et al. (2003) Structure-based de novo design, synthesis, and biological evaluation of non-azole inhibitors specific for lano-sterol 14alpha-demethylase of fungi. J. Med. Chem. 46, 474—485. 

MAO is a much less discriminating enzyme in that it will catalyze the removal of an amine group from a variety of substrates. The action of MAO on norepinephrine and epinephrine also is indicated in Figure 9.5. The list of its substrates is very large, including endogenous substances (norepinephrine, epinephrine, dopamine, tyramine, 5-hydroxy-tryptamine) and many drugs that are amines. At least in the brain, two separate forms of MAO have been described MAO type A and MAO type B. The two types are differentiated on the basis of substrate and inhibitor specificity. 

In the late 1960s, two groups reported results that indicated the possibility of more than one form of MAO. In 1967, Maitre suggested that tissue (brain vs liver)-dependent potencies of inhibitors could be explained by the presence of different forms of MAO [4]. In 1968, Johnston published an analysis of unusual kinetics observed with the new MAO inhibitors that were being developed. He concluded that the most reasonable hypothesis to explain such results as double sigmoid curves was the existence of at least two forms of the enzyme [5]. By the mid-1980s, differences of substrate and inhibitor specificity of two MAOs, now called MAO A and B, were well understood [6]. 

Very few inhibitors specifically target HIV-1 RNase H activity. Illimaquinone, a natural marine product, was shown to preferentially inhibit the HIV-1 RNase H activity [113,114]. However, this compound appears to react with a sulfhydryl group in the polymerase domain and not with RNase H itself. It may be possible to use the available information on structural and biochemi-... 

---