Activated complex component side chains

Esters of diphenylacetic acids with derivatives of ethanol-amine show mainly the antispasmodic component of the atropine complex of biologic activities. As such they find use in treatment of the resolution of various spastic conditions such as, for example, gastrointestinal spasms. The prototype in this series, adiphenine (47), is obtained by treatment of diphenyl acetyl chloride with diethylaminoethanol. A somewhat more complex basic side chain is accessible by an interesting rearrangement. Reductive amination of furfural (42) results in reduction of the heterocyclic ring as well and formation of the aminomethyltetrahydro-furan (43). Treatment of this ether with hydrogen bromide in acetic acid leads to the hydroxypiperidine (45), possibly by the intermediacy of a carbonium ion such as 44. Acylation of the alcohol with diphenylacetyl chloride gives piperidolate (46). ... 

These defects have spurred attempts to prepare analogs. The techniques used have been (1) natural fermentation (in which the penicillin-producing fungus is allowed to grow on a variety of complex natural nutrients from which it selects acids for incorporation into the side chain), (2) biosynthetic production (in which the fermentation medium is deliberately supplemented with unnatural precursors from which the fungus selects components for the synthesis of "unnatural" penicillins), (3) semisynthetic production (in which 6-aminopenicillanic acid (2) is obtained by a process involving fermentation, and suitably activated acids are subsequently reacted chemically with 6-APA to form penicillins with new side chains) and (4) total synthesis (potentially the most powerful method for making deep-seated structural modifications but which is at present unable to compete economically with the other methods). 

A key contribution of molecular dynamics simulations to the imderstanding of mechanisms of selectivity and affinity in TBP-DNA complexes is the discovery of the active role of TBP in the formation of the complex. The view derived from crystal structures was that of a passive role for the TBP which only imposed a steric constraint on DNA shape. It appears now from the simulations that TBP can respond to the dynamics of the bound DNA sequence by adjusting its interdomain geometry, and this might be relevant for the construction of the final preinitiation complex. Furthermore, many of the contacts characterized in the crystal structures were found in the simulations to have an important dynamic component, as side chains switch rotamers rather frequently. This conformational freedom makes it possible for TBP to achieve suitable binding contacts with a variety of DNA moieties in a dynamic mode which contributes to enthalpic stabilization. However, the extent of preservation of side chain dynamics in the complex is dependent on the local structure. As it reduces the entropy loss upon complex formation, it provides an additional source of sequence-dependent gain in affinity that is revealed for the first time from the results of the molecular dynamics simulations. 

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