Paclitaxel tubulin binding mechanism

Peluroside A was the first microtubule stabilizing agent whose conformation has been determined bound to microtubules (those of Paclitaxel and Epothilone were determined in non-microtubular tubulin [5, 12, 38, 91]). In the bound state, the NMR data, assisted by molecular mechanics calculations and docking experiments, indicated that only one (that present in water, B) of the two major conformations existing in water solution is bound to microtubules (a-tubulin). A model of the binding mode to tubulin has also been proposed [27], involving the a-tubulin monomer, in contrast with paclitaxel, which binds to the p-monomcr. 

EXPLORATION ON MECHANISM OF PACLITAXEL RELATED TO TUBULIN BINDING AND QUEST FOR ITS PHARMACOPHORE... 

Vinca alkaloids (vincristine, vinblastine, vinorelbine) are derived from the periwinkle plant (Vinca rosea). These agents work by binding to tubulin at a site different than colchicine or paclitaxel. They block polymerization, which prevents the formation of the mitotic spindle, and are used as antineoplastic agents. Taxanes produce a stabilization of microtubules similar to colchicine, but by a different mechanism, and also halt cells in metaphase. Paclitaxel (taxol) is the taxane used clinically. It is derived from the bark of the pacific yew. Taxol disrupts several microtubule-based functions as completely as inhibitors of polymerization, emphasizing the importance of assembly/disassembly balance in microtubule function. Recently, it has been found that paclitaxel also binds to and inhibits the function of a protein called bcl-2, an inhibitor of one or more pathways involved in mediating apoptosis. PaclitaxeTs interference with this function promotes apoptosis in addition to its microtubule-related inhibition of cell division. 

Paclitaxel and docetaxel have been shown to act as spindle poisons, causing cell division cycle arrest, based on a unique mechanism of action.7-10 These drugs bind to the P-subunit of the tubulin heterodimer, the key constituent protein of cellular microtubules (spindles). The binding of these drugs accelerates the tubulin polymerization, but at the same time stabilizes the resultant microtubules, thereby inhibiting their depolymerization. The inhibition of microtubule depolymerization between the prophase and anaphase of mitosis results in the arrest of the cell division cycle, which eventually leads to the apoptosis of cancer cells. 

The natural product eleutherobin (1) was isolated in 1994 by Fenical et al. from a marine soft coral from an Eleutherobia species and its structure was elucidated shortly afterwards (Figure 1) [1]. Eleutherobin is a diterpene glycoside that possesses remarkable cytotoxicity against a wide variety of cancer cells, which is likely to be based on binding to tubulin and stabilization of microtubules [2, 3]. Mitosis is interrupted and the cell division cycle is terminated. The mechanism of action of eleutherobin is comparable to that of highly potent cytostatic agents such as paclitaxel (Taxol), nonataxel, epothilones, and discodermolide. 

Although this mechanism cannot explain microtubule induced assembly in conditions in which tubulin is unable to assemble in absence of ligands, the ligand facilitated pathway is supported by the fact that paclitaxel does not bind tightly to unassembled tubulin (at least under non-assembly conditions) [33]. 

The study of the tubulin-bound conformation of paclitaxel has resulted in a number of protein-ligand models, partially or fully based on the electron diffraction structure of aP-tubulin in paclitaxel-stabilized Zn2+-induced sheets [5, 12], Obviously, the nature of the paclitaxel binding site and the paclitaxel conformation in the binding site have key implications for the design of new MSA. A deep knowledge of the bioactive conformation would also help to explain how compounds as structurally diverse as the epothilones [48], discodermolide [49], and eleutherobin [50] have very similar mechanisms of action. 

Most research has focused on the development of paclitaxel analogs or prodrugs with enhanced specificity MDR reversal and orally effective taxoids have also been developed recently. Meanwhile, scientists have gained insights into the mechanism of action of taxoids at molecular level, that is, binding sites on tubulin and dynamics of tubulin polymerization. It is worth pointing out that the SAR results derived from traditional medicinal chemistry have shown the essential... 

A group of mitotic inhibitors (vinblastine, vincristine, and vinorelbine) exert their cytotoxic effects by binding to tubulin. This inhibits formation of microtubules, causing metaphase arrest. Their mechanism of action and metabolism are similar, but the antitumor spectrum, dose and clinical toxicities of vinblastine, vincristine, and vinorelbine are very different. Paclitaxel and docetaxel are also mitotic inhibitors. However, they differ from the vinca alkaloids by enhancing microtubule formation. As a result, a stable and nonfunctional microtubule is produced. 

The mechanism of action of paclitaxel involves its binding to the p-subunit of a,P-tubulin dimer, accelerating the formation of microtubules. The resulting paclitaxel-bound microtubules are much more stable and less dynamic than the natural GTP-bound micro-... 

The mechanism of action of the vinca alkaloids is that of the inhibition of the polymerization of tubulin to microtubules. The cellular protein tubulin, which occurs in a- and /3-forms, is essential for proper cellular function. During mitosis tubulin polymerizes to form microtubules, which are long tube-shaped protein polymers. The equilibrium between unpolymerized a- and /3-tubulin and microtubules is an important one and any disruption of this equilibrium can send dividing cells into mitotic block and apoptosis. The vinca alkaloids bind to /3-tubulin at a different site from paclitaxel (Taxol) and act to prevent tubulin assembly. 

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