Weak competitive inhibitor

The drug SC-558 acts by a fourth mechanism, specifically inhibiting COX-2. It is a weak competitive inhibitor of COX-1 but inhibits COX-2 in a slow, time-dependent process. Specific COX-2 inhibitors will likely be the drugs of the future because they selectively block the inflammation mediated by COX-2, without the potential for stomach lesions and renal toxicity that arise from COX-1 inhibition. 

Diacylglycerol has long been known to be a weak competitive inhibitor of PLC/fc, whereas phosphorylcholine shows very little inhibition [40, 49, 116]. Recent kinetic assays of PLCB(. activity in the presence of DAG indicate that it is a competitive inhibitor with a Kl of the order of 10 mM, whereas phosphorylcholine was found to be an extremely weak (K = 30-50 mM), mixed inhibitor of PLC/J( [34]. Because diacylglycerol is a competitive inhibitor of the enzyme, the nature of the catalytic cycle dictates that it must be the last product to leave the enzyme active site. 

T. B. Mercer, S. F. Jenkinson, B. Bartholomew, R. J. Nash, S. Miyauchi, A. Kato, and G. W. J. Fleet, Looking glass inhibitors Bote enantiomeric IV-benzyl derivatives of l,4-dideoxy-l,4-imino-D-lyxitol (a potent competitive inhibitor of a-D-galactosidase) and of l,4-dideoxy-l,4-imino-L-lyxitol (a weak competitive inhibitor of a-D-galactosidase) inhibit naringinase, an a-L-rhamnosidase competitively, Tetrahedron Asymmetry, 20 (2009) 2368-2373. 

Compound VI was found by Wedler and Horn to be a weak competitive inhibitor of the enzyme with a dissociation constant of 3 mAf. This compound should mimic the /-glutamyl phosphate intermediate (II). From this... 

The requirement of the remaining enzymes, KD0-8-phosphate synthase, KD0-8-phosphate phosphatase and CMP-KDO synthetase, for their natural substrates, D-arabinose-5-phosphate + PEP, KD0-8-phosphate and KDO + CTP, respectively, was specific and the inhibition studies with substrate analogues were disappointing. Of the compounds tested as potential substrates of KD0-8-phosphate synthase, only the isosteric phosphonate analogue (Compound 11, Table III) of D-arabinose-5-phosphate was an alternate substrate (see Ref. 28). There were a number of weak competitive inhibitors of the synthase reaction (Compounds 2, 5, 6, 7, 15,and 19,Table III) the best inhibitor of the synthase reaction was 2-deoxy-2-fluoro-D-arabinonate-5-phosphate (compound 14, Table III). 

The Km value also affects the substrate concentration employed in the assay. The assay is more sensitive to weak competitive inhibitors when working at low substrate concentrations. In drug discovery, protease assays are usually run with substrate concentrations at or below the KM value, because the focus is mainly on the identification and characterization of competitive inhibitors (Cheng and Prusoff, 1973 Copeland, 2005). The turnover number kcat is a first-order rate constant that defines the maximum number of substrate molecules converted to product per time unit under saturating conditions (i.e., at high excess of substrate). 

Initial design of the inhibitors was based on a rational design strategy using the renin substrate as a starting point. Some of the early studies indicated that the octapeptide of horse angiotensinogen (His-Pro-Phe-His-Leu-Leu-Val-Tyr), cleaved slowly by renin between the two leucine residues, was a weak competitive inhibitor of renin. This led to the modifications in the P, and P, positions (Leu-Leu) of this peptide. The early work indicated that the two leucine residues could be replaced by... 

Finally, 4p,5p-epoxyandrostenedione as well as its 19-hydroxy and 19-oxo derivatives have been examined as aromatase inhibitors. The epoxides were found to be weak competitive inhibitors, whereas the 19-hydroxy and 19-oxo derivatives were largely ineffective . 

The purple acid phosphatases are typically assayed by their ability to hydrolyze p-nitrophenylphosphate. The K values for this substrate are in the millimolar range (171b, 174). The product phosphate and its analogue arsenate are weak competitive inhibitors (A mM) in addition, they potentiate the conversion of the diiron enzymes under aerobic conditions to an irreversibly inactivated, oxidized form (45, 185-187). Other tetraoxo anions such as molybdate and tungstate, on the other hand, are tightly bound inhibitors K, xM) which do not potentiate the oxidation of the diiron enzymes (185, 186). Interestingly, the FeZn forms are similarly inhibited by these anions with comparable K, values, but are not susceptible to the oxidative inactivation observed for the diiron derivatives (185). 

Addition of methyl groups to either one or both of the ethylene carbons results in chiral molecules. Muscarinic receptors (see below) display stereoselectivity for the enantiomers of methacholine. The S-(+)-enantiomer is equipotent with acetylcholine, and the R-(-)-enantiomer is approximately 20-fold less potent. Acetylcholinesterase hydrolyzes the S-(+)-isomer much slower (approximately half the rate) than acetylcholine. The R-(-)-isomer is not hydrolyzed by AChE and even acts as a weak competitive inhibitor of the enzyme. This stability toward AChE hydrolysis as well as the AChE inhibitory effect of the R-(-)-enantiomer may explain why racemic methacholine produces a longer duration of action than acetylcholine. The nicotinic receptor and AChE exhibit little stereoselectivity for the optical isomers of acetyl-a-methylcholine. 

Inhibition by four isomeric 2-acetamido-2,3-dideoxy-D-hex-2-enonolactones viz. 2-acetamido-2,3-dideoxy-D-eryr o- and -D-/Areo-hex-2-enono-l,4-lactones and the corresponding 1,5-lactones) of the j8-D-2-acetamido-2-deoxyglucosidase from bovine epididymus has been examined. The o-ery/Aro-lactones were shown to be weak competitive inhibitors, whereas the D-//jreo-lactones were inactive. The activity of 2-acetamido-2,3-dideoxy-D-eryr ro-hex-2-enono-1,4-lactone against this enzyme from a number of animal and plant sources was also tested, although 2-acetamido-l,5-anhydro-2-deoxy-D-ara6mu- and -L.-lyxo-hex-l-enitol were much more effective inhibitors. 

Substrate analogs S-Adenosylhomocysteine (AdoHcy), the reaction product of AdoMet (see Scheme 4.2), binds the enzyme to form a binary complex (Kj = 225 juM) and is a weak competitive inhibitor (K = 9.0 ptM) (4). Sinefungin, a natural analog of AdoMet in which the methyl sulfonium (CH3-S <) group is replaced with an amine methine (NH2-CH<), is a potent inhibitor the of the binary complex is 4.3 jiiM and the (competitive) is 10 nM (4). Inhibition with sinefungin occurs via formation of a stable, sequence-specific ternary complex (MTase-DNA-sinefungin). N-Methyl- and N-ethyl-AdoMet bind M- coRl weakly and are poor inhibitors. 

Vanadate is a strong inhibitor of BAP with a K, of 2—3 pM (13). Phenol enhances vanadate inhibition in the hydrolysis of PNPP, presumably by forming a phenyl vanadate ester [K- = 0.2 pM) which has a greater affinity for the enzyme than the vanadate alone. Note that phenol by itself is a weak competitive inhibitor with a /Cj of 180 mM. For other metal ions, inhibition decreases in the order of tungstate (WO ", Kj = 6 pM) > arsenate (AsO ", = 3—20 pM) > molybdate... 

A number of C-2 functionalized ddA analogs were also synthesized by us. Representative structures are shown in Scheme 3. Compounds 3 were almost totally resistant to deamination by ADA. They were, however, moderate to weak competitive inhibitors of this enzyme with K. values ranging from 10 to 10. Antiviral studies revealed that they were inactive up to 200 pM in MT-4 cells. 

---