Vinca alkaloid binding site

Molecular Modeling on Compounds Targeting the Vinca Alkaloid Binding Site... 

Dolastatins are a class of peptides comprised of mostly nonribosomal amino acids. They were isolated from a sea hare Dolabella auricularia (94). Dolastatin-10 (86) is one of the most potent and the best-studied members (95, 96). It exerts it antitumor effect by inhibiting tubulin polymerization and binds at the vinca alkaloid binding site (97, 98). Dolastatin-10 has been studied in Phase II human clinical trials but was discontinued because of lack of efficacy (99). Auristatin PE... 

Vinca alkaloids such as vinblastine (2) are also known to bind tubulin. Competitive reagents along with fluorescent and fluorescent photoaffinity analogues of vinblastine (2) were synthesised in an attempt to determine the vinca alkaloid binding site. Residues 12, 201, 211,175-213, and 363-379 of p-tubulin were implicated in the binding of this compound as... 

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. 

Vincristine and vinblastine (vinca alkaloids) comprise another class of drugs that inhibit the polymerization of microtubules but do so by binding to the tubulin molecule at a site different from the colchicine site. Cultured cells exposed to high concentrations of vinca alkaloids develop intracytoplasmic paracrystalline aggregates of tubulin. These drugs are employed clinically in cancer chemotherapy to inhibit the growth of tumors composed of rapidly dividing cells. 

The cause of the cell cycle specificity of the bisindole alkaloids may be associated with the ability of these compounds to interact with the protein tubulin and thereby inhibit the polymerization (and depolymerization) of microtubules (16,17). In this respect the cellular pharmacology of vinca alkaloids is similar to that of other cytotoxic natural products such as colchicine or podophyllotoxin. On closer inspection, however, Wilson determined that the specific binding site on tubulin occupied by vinblastine or vincristine is chemically distinct from the site occupied by the other natural products (18). Subsequent experiments have determined that the maytansinoids, a class of ansa-macrocycles structurally distinct from the bisindoles, may bind to tubulin at an adjacent (or overlapping) site (19). A partial correlation of the antimitotic activity of these compounds with their tubulin binding properties has been made, but discrepancies in cellular uptake probably preclude any quantitative relationship of these effects (20). 

Bai, R., Pettit, G. R., and Hamel, E. (1990). Binding of dolastatin 10 to tubulin at exchangeable nucleotide and Vinca alkaloid sites. J. Biol. Chem. 265,17141-17149. 

Ferry DR, Russell MA, Cullen MH. P-glycoprotein possesses a 1,4-dihydropyr-idine-selective drug acceptor site which is alloserically coupled to a vinca-alkaloid-selective binding site. Biochem Biophys Res Commun 1992 188(1 ) 44(M145. 

The exact binding site of vinca alkaloids remained unknown until 2005, when the crystal structure of vinblastine bound to tubulin complexed with colchicine and with the stathmin-like domain of RB3 was determined (PDB entry 1Z2B) [3], The structure revealed that vinblastine binds to curved tubulin at the interface between two a/p-tubulin heterodimers (interdimer interface, Fig. 4), introducing a wedge that interferes with tubulin assembly. The vinblastine binding site is defined by loop T7, helix H10 and strand S9 in the a subunit of the first heterodimer, and by helix H6 and loops T5 and H6-H7 in the p subunit of the second heterodimer. In microtubules, this region is located toward the inner lumen and is... 

Site of action Paclitaxel binds reversibly to tubulin, but unlike the vinca alkaloids, it promotes polymerization and stabilization of the polymer rather than disassembly (Figure 38.15). Thus it shifts the depolymerization-polymerization to favor the formation of microtubules. The overly stable microtubules formed in the presence of paclitaxel are dysfunctional, thereby causing the death of the cell. 

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. 

The first compound of the taxanes series, paclitaxel (Taxol), was isolated from the bark of the Western yew tree in 1971. It and its congenic, the semisynthetic docetaxel (Taxotere), exhibit unique pharmacological actions as inhibitors of mitosis, differing from the vinca alkaloids and colchicine derivatives in that they bind to a different site on P-tubulin and promote rather than inhibit microtubule formation. The drugs have a central role in the therapy of ovarian, breast, lung, esophageal, bladder, and head and neck cancers. 

Vinblastine (2) and several vinca-related drugs bind to a different site, as do a number of other drugs that bind competitively with each other, but do not compete with the colchicinoids. Like the colchinoids, vinca alkaloids destabilise microtubules. The Taxol (3) binding site is located in a pocket that is lined by several hydrophobic residues and is well defined from crystal structures of aP-tubulin. It represents the putative binding site for other microtubule stabilising drugs like epothilones [2,11]. 

Other binding sites have been postulated according to tubulin interfering agents with a binding behaviour distinct to that of taxanes, vinca alkaloids and colchinoids. 

VINCA SITE BINDING AGENTS Vinca Alkaloids... 

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