Alternative binding mode

Predictive power using limited exploration of alternate binding modes. 

Predictive power using limited exploration of alternate binding modes./. Med. Chem. 1994, 37, 2206-2215. 

Pastor, M., Perez, C., and Gago, F. (1997) Simulation of alternative binding modes in a structure-based QSAR study of HIV-1 protease inhibitors.. /. Mol. Graph. Model. 15, 364-371. 

Oprea, T. I., Waller, C. L., and Marshall, G. R. (1994). Three dimensional quantitative structure-activity relationship of human immunodeficiency virus (I) Protease inhibitors. 2. Predictive power using limited exploration of alternate binding modes../. Med. Chem. 37, 2206-2215. 

The difference in the preferred binding mode observed for the Pd- and Ni-based catalysts can be the crucial factor determining activity/inactivity of these two systems in polar copolymerization. However, the question arises about the stability of the alternative binding modes at finite temperature. If the minima were separated by relatively low barriers and fast interconversion between the two isomer complexes could occur, then this difference would be of minor importance. In order to check the stability of the two modes and get the insight into the mechanism of possible interconversions, a series of molecular dynamics simulations was performed. 

Other Complexes. Before we turn to a discussion of other complexes, it is worth making a few general comments about the biomimetic systems studied to date. The model systems are much slower ( 105-fold) than the enzyme (33). All peroxovanadium complexes, whether competent to catalyze bromide oxidation reactions or not, contain tj2-coordinated peroxide (4). Little is known about the binding of peroxide in the enzyme (see above), but one wonders whether the enhanced reactivity is derived from an alternative binding mode, such as end-on peroxide or hydroperoxide. The rapid enzymatic rate could also arise from the nature or configuration of the ligands to the vanadium ion. 

One of the difficulties with this type of approach is that the quality of the results depends directly on the quality of the initial pharmacophore model, which can sometimes prove challenging. A particular hazard is that active compounds can have different binding modes, even in a closely related series of inhibitors. This algorithm partially addresses that problem, since it does not take as a fundamental assumption that all molecules bind in the same orientation, however further tools to identify alternative binding modes would be helpful. Overall it shows potential to be a powerful tool to direct library design. 

Crystal structures of steroid receptors in complex with synthetic ligands have revealed alternative binding modes as compared to the natural steroid hormone. To date, ERa and ERyS subtypes [32] have provided the most variety of crystal structures with bound synthetic ligands [33], There are currently several examples of ER in complex with synthetic ligands diethylstilbestrol (DES), 4-hydroxytamoxifen (OHT) [34], genestein [35], raloxifene [36],... 

Fig. 17.1 Interaction capacities of the natural R +)-epinephrine and its S(-)-antipode. In simply assuming that the natural R(+)-epinephrine establishes a three point interaction with its receptor (A) the combination of the donor-acceptor interaction, the hydrogen bond and the ionic interaction will be able to generate energies in the order 12 to 17 kcal mole that corresponds to binding constants of 10 to 10 The less active isomer, S(+)-epinephrine, may establish only a two point contact (B). The loss of the hydrogen bond interaction equals to approximately 3 kcal mole this isomer should therefore possess an approximately 100-fold lesser affinity. The experience confirms this estimate. If we consider less abstract models it becomes apparent that the less potent enantiomer is also able to develop three intermolecular bonds to the receptor, provided that it approaches the receptor in a different manner. However, the probability of this alternative binding mode to trigger the same biological response is close to null.

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