Finding Weak Inhibitors

Successful Identification of Novel Leads through Virtual Screening 

It has been shown that virtual screening is an efficient way of finding novel leads. The program DOCK, one of the most widely used docking programs, has been applied in many published 

To overcome the limitations of known DNA gyrase inhibitors, a new drug discovery project was inititated at Roche. Searching for novel inhibitors by screening the Roche compound library provided no suitable lead structures. 

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Bhandari et al. (56) modified a hit structure derived from the primary screening of various libraries (>300,000 compounds) on the zinc metalloenzyme phosphomannose isomerase from the yeast Candida albicans (CaPMI) to find enzyme inhibitors as jxitential antifungal agents. During primary screening only a 1296-member SP dipeptide pool library (Lll, Fig. 9.16) showed activity on the enzyme. Its deconvolution and analytical characterization led to the discovery of a by-product, derived from incomplete coupling, that showed activity on the enzyme. This compound (9.21, Fig. 9.16) showed a weak inhibitory activity on CaPMI (ICso = 40 xM) and was selected for further chemical profiling. 

Many compounds have been studied as possible inhibitors of diamine oxidase because of the finding that the so-called antihistamine drugs inhibit diamine oxidase. Ammonia (190), aliphatic monoamines (191), ephed-rine (199), and choline (191) are weak inhibitors, whereas guanidines (193), imidazole (194), basic dyes such as pyocyanine (195), methylene blue (196), and toluylene blue (195), diamines such as thiamine (197), pyridoxamine (197), piperazine (197), and diamidines (198) (such as 4,4 -diamidinostilbene and its dimethyl derivative) are potent competitive... 

It is necessary to use the weak inhibitor method for controlling the molecular weight of polymethyl methacrylate in batch bulk polymerization. At 60°C kp is 580 L/mol sec, whereas the value of for terephthonitrile is 31.2. Assume that [I2] = lO mol/L and find in problem. 

It was shown previously (24) that KD0-8-phosphate was a weak end-product inhibitor of the synthase reaction. Both of the end products of this reaction, KDO and inorganic phosphate are weak mixed-function inhibitors of KD0-8-phosphate phosphatase. The reduced form of KD0-8-phosphate (the C-2 carbonyl was reduced to the corresponding diasterioisomeric alcohol with NaBH, Table V, 3 red.), an open chain analogue, was neither an inhibitor of KD0-8-phosphate synthase nor was it a substrate or inhibitor of the phosphatase reaction. These findings indicate that the mechanism of KD0-8-phosphate synthase does not involve the formation of a linear intermediate and that the KD0-8-phosphate phosphatase requires the phosphorylated substrate in the ring form rather than the linear form. 

Some years ago a benzothiophene that exhibited some activity as a tubulin polymerization inhibitor and appeared to bind weakly to the colchicine binding domain of tubulin was reported. This finding stimulated the synthesis of several benzofuran and indole analogues, Fig. (17). 

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