Associative mechanism from volumes activation

Substances that do not target the active site but display inhibition by allosteric mechanisms are associated with a lower risk of unwanted interference with related cellular enzymes. Allosteric inhibition of the viral polymerase is employed in the case of HIV-1 nonnucleosidic RT inhibitors (NNRTl, see chapter by Zimmermann et al., this volume) bind outside the RT active site and act by blocking a conformational change of the enzyme essential for catalysis. A potential disadvantage of targeting regions distant from the active site is that these may be subject to a lower selective pressure for sequence conservation than the active site itself, which can lower the threshold for escape of the virus by mutation. 

The replacement of X by pyridine in the complex PtX(dien)+ to give Pt(dien)py2+ (equation 549) has been studied under controlled conditions with a range of leaving groups X. These data are shown in Table is.1 87-1988 From these data the leaving group order is NOj > H20 > Cl- > Br > I- > N3 > SCN- > NO2 > CN-. Reactions such as these must be carried out under thermal conditions for accurate comparison since photoaquation can occur, albeit with a rather low quantum yield.1989 The volumes of activation of these reactions (equation 550) are all negative. An associative mechanism is proposed for the nucleophilic dependent path, but for the nucleophile independent pathway both associative and dissociative mechanisms need to be considered.1990... 

The second-order term in the rate laws for reactions of low-spin iron(II) diimine complexes with such nucleophiles as hydroxide and cyanide ions has been established as arising from a bimolecular reaction between complex and nucleophile.182 Activation volumes that were obtained for reactions of CN and OH with Fc(phcn)2 1 and Fe(bpy)3 + were in the range of +19.7 to +21.5cm3mol-1.183 Because these observations were not readily accounted for by an associative mechanism, a mechanism analogous to the Eigen-Wilkins mechanism of complex formation was introduced in which dissociative activation dominates in determining the observed activation volumes. However, subsequently it was shown that solvation... 

It is convenient for a simplified analysis of activation volumes to consider octahedral complexes as essentially incompressible spherical species with a characteristic average radius. It has been assumed that a five coordinate intermediate (MLj) arising from the dissociative release of a neutral ligand (L) will occupy the same volume as its six-coordinate precursor MLg. The volume of [NiCNHj) ] (138 cm mof ) is identical to that calculated for the hypothetical [Ni(NH3)5] cation. For the analogous cobalt(III) system, the intermediate [Co(NH3)5] has been estimated to have the same volume as [Co(NH3)g] (55 cm mof ). In the case of an associative mechanism the seven coordinate intermediate (ML7) is believed to occupy the same intrinsic volume as its precursor MLg. 

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