ABSTRACT
Based on the high-resolution X-ray crystallographic structure of phospholipase C from Bacillus cereus, the orientation of the phosphatidylcholine substrate in the active site of the enzyme is proposed. The proposal is based on extensive calculations using the GRID program and molecular mechanics geometry relaxations. The substrate model has been constructed by successively placing phosphate, choline and diacylglycerol moieties in the positions indicated from GRID calculations. On the basis of the resulting orientation of a complete phosphatidylcholine molecule, we propose a mechanism for the hydrolysis of the substrate.
Subject(s)
Computer Simulation , Type C Phospholipases/metabolism , Binding Sites , Catalysis , Models, Molecular , Oxygen/chemistry , Phosphates/chemistry , Quaternary Ammonium Compounds/chemistry , Software , Substrate Specificity , Type C Phospholipases/chemistry , Zinc/metabolismABSTRACT
A molecular modelling and computer graphics study of a series of pyrethroid insecticides has been carried out. The three-dimensional arrangement of the groups essential for the biological activity (pharmacophore) has been identified for the acid and the alcohol moieties, respectively. These pharmacophores are based on the relationship between molecular structure and biological activity for a number of pyrethroid esters. The pharmacophores, which describe the relative location in space of the unsaturated systems, the dimethyl groups and the ester moiety, may be useful in the design of novel compounds with pyrethroid activity.
Subject(s)
Models, Molecular , Pyrethrins , Binding Sites , Computer Graphics , Drug Design , Structure-Activity RelationshipABSTRACT
3-Isoxazolols substituted in the 5-position by pyrrolidinyl or piperidyl (referred to, respectively, as PYOLs and PIOLs; see Figure 2 for structures) were designed and synthesized as analogues of the potent and specific GABAA agonist THIP. Activity in the series was markedly dependent upon positional isomerism in the structures. Isomers in which the pyrrolidine or piperidine rings were attached via their 2-positions (2-PYOL and 2-PIOL) had no effect on GABAA receptors in vivo or in vitro. An isomer wherein attachment was via the 4-position (4-PIOL) was a GABAA agonist, but it was unique in not affecting the binding of diazepam in vitro; its 'ring-opened' analogue, (RS)-5-(1-methyl-3-aminopropyl)-3-isoxazolol (11) did not bind significantly to GABAA receptor sites in vitro. In contrast, the 3-positional isomer (3-PIOL) antagonized the inhibitory action of glycine on cat spinal neurons. A similar effect was earlier demonstrated for 3-PYOL. However, in contrast to 3-PYOL, which is approximately equipotent as an antagonist of glycine and GABA, 3-PIOL only marginally reduced the inhibitory effect of GABA. The R and S forms of 3-PIOL, synthesized from the respective isomers of piperidine-3-carboxylic acid with known absolute stereochemistry, had pharmacological profiles indistinguishable from that of racemic 3-PIOL.