Laulimalide binding site

Fig. 25 Comparison of the predicted hydrophobicity of a laulimalide b epothilone B c pacli-taxel. Structures a and b correspond to a common solution conformation for the two macrolides. Solvent accessible surfaces are colored according to the degree of hydrophobicity brown hydro-phobic, green neutral, blue hydrophilic, d Laulimalide binding site on (1-tubulin- after (3—H9 movement described in text. The view is from the outside of the microtubule. The paclitaxel (PTX) site is labeled too, but it is accessed from the lumen...

Finally, the NMR-derived bioactive conformation was docked onto the EC-derived coordinates of tubulin in an attempt to find the laulimalide/peloruside binding site. The EC-derived coordinates of tubulin (PDB entry 1TUB) were used for the docking. The preferred binding region was found in the a subunit, in a site close to that found previously in the computational study by Pineda et al. [16]. This binding site is formed by helix H7, and loops S9-S10 and H1-S2 (Fig. 30). It is remarkable... 

The framework for this discussion will be formed around three important classes of MT stabilizers shown in Scheme 1. Given the chemical similarity between epothilones and laulimalide, it is particularly surprising that, while taxanes and epothilones compete for the same binding site, laulimalide has been shown to be non-competitive with either. In fact, laulimalide may bind simultaneously with taxanes and produce a synergistic effect. This chapter provides details of experiments and analyses we have done to formulate and test hypotheses about these binding mechanisms. 

Laulimalide is also active in P-glycoprotein overexpressing cells [129]. Despite these similarities, laulimalide does not bind the paclitaxel binding site... 

By means of AutoDock [134] and Gold software [135], laulimalide, peloruside and paclitaxel were docked in this structure, but only the former two compounds were able to give profitable interactions, mainly because of the overall size of the ligands. Nevertheless, the calculated binding energies for laulimalide and peloruside into the paclitaxel binding site were favorable to interaction, as well as the binding predictions performed with the pseudoreceptor model [133],... 

To overcome the intrinsic limitation of the pseudoreceptor built on the basis of paclitaxel binding site, a 5D-QSAR [83] model was built, further suggesting a preference for the P-subunit binding site. Results suggest that a multi-site binding is possible, indicating that laulimalide and peloruside can secondarily bind the paclitaxel binding site. 

These include rhazinilam (15.4.6) 494), which inhibits the disassembly of microtubules but has a different mechanism of action than taxol, laulimalide (15.4.7) and isolaulimalide (15.4.8) 496), WS9885B (15.4.9) 497), and polyisoprenylated benzophenones such as guttiferone E (15.4.10) 497). The naturally occurring 3(2H)-furanone derivative geiparvin has been found to counteract the microtubule-assembly effects of taxol, suggesting that it is a competitive inhibitor at the taxol-binding site of tubulin 498). 

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