Pharmacophore Models of Paclitaxel- and Epothilone-Based Microtubule Stabilizing Agents (original) (raw)
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Antimicrobial agents and chemotherapy, 1996
Trifluralin, a dinitroaniline microtubule inhibitor currently in use as an herbicide, has been shown to inhibit the proliferation of Plasmodium falciparum, Trypanosoma brucei, and several species of Leishmania, in vitro. As a topical formulation, trifluralin is also effective in vivo (in BALB/c mice) against Leishmania major and Leishmania mexicana. Although trifluralin and other dinitroaniline herbicides show significant activity as antiparasitic compounds, disputed indications of potential carcinogenicity will probably limit advanced development of these substances. However, researchers have suggested that the activity of trifluralin is due to an impurity or contaminant, not to trifluralin itself. We have pursued this lead and identified the structure of the active impurity. This compound, chloralin, is 100 times more active than trifluralin. On the basis of its structure, we developed a rational structure-activity model for chloralin. Using this model, we have successfully predic...
Dissecting Paclitaxel–Microtubule Association: Quantitative Assessment of the 2′-OH Group
Biochemistry, 2013
Paclitaxel (PTX) is a microtubule-stabilizing agent that is widely used in cancer chemotherapy. This structurally complex natural product acts by binding to β-tubulin in assembled microtubules. The 2′-hydroxyl group in the flexible side chain of PTX is an absolute requirement for activity, but its precise role in the drug−receptor interaction has not been specifically investigated. The contribution of the 2′-OH group to the affinity and tubulin-assembly efficacy of PTX has been evaluated through quantitative analysis of PTX derivatives possessing side chain deletions: 2′-deoxy-PTX, N-debenzoyl-2′-deoxy-PTX, and baccatin III. The affinity of 2′-deoxy-PTX for stabilized microtubules was more than 100-fold lower than that of PTX and only ∼3-fold greater than the microtubule affinity of baccatin III. No microtubule binding activity was detected for the analogue N-debenzoyl-2′-deoxy-PTX. The tubulin-assembly efficacy of each ligand was consistent with the microtubule binding affinity, as was the trend in cytotoxicities. Molecular dynamics simulations revealed that the 2′-OH group of PTX can form a persistent hydrogen bond with D26 within the microtubule binding site. The absence of this interaction between 2′-deoxy-PTX and the receptor can account for the difference in binding free energy. Computational analyses also provide a possible explanation for why N-debenzoyl-2′-deoxy-PTX is inactive, in spite of the fact that it is essentially a substituted baccatin III. We propose that the hydrogen bonding interaction between the 2′-OH group and D26 is the most important stabilizing interaction that PTX forms with tubulin in the region of the C-13 side chain. We further hypothesize that the substituents at the 3′-position function to orient the 2′-OH group for a productive hydrogen bonding interaction with the protein.
Chemistry & Biology, 2004
gicas their good activity against ovarian, metastatic breast, head and neck, and lung cancer [4], paclitaxel has two Consejo Superior de Investigaciones Científicas Ramiro de Maeztu 9 factors that hamper its applicability. First, its low aqueous solubility, and second, the development of pleiotro-28040 Madrid Spain pic drug resistance mediated both by the overexpression of the P-glycoprotein [5, 6] and the presence of mutations in -tubulin [7, 8]. The discovery in recent years of several natural sub-Atlanta, Georgia 30322 3 Department of Chemistry and stances with a paclitaxel-like mechanism of action (epothilone, discodermolide, laulimalide, eleutherobin, The Skaggs Institute for Chemical Biology The Scripps Research Institute peloruside, dictyostatin-1, taccalonolide, and jatrophane polyesters; [9-16]) opened new possibilities in 10550 North Torrey Pines Road La Jolla, California 92037 the field. Of these compounds, the first one recognized as having a paclitaxel-like activity was an already known natural compound called epothilone [9], a secondary metabolite from the soil myxobacterium Sorangium cel-9500 Gilman Drive La Jolla, California 92093 lulosum [17-19]. Epothilones are the most promising of this group of new paclitaxel-like compounds because they offer several advantages. First of all, while most of the other compounds are isolated from marine organ-Summary isms in limited amounts, epothilone B can be obtained in kilogram amounts by fermentation [20]. Second, it The interactions of epothilone analogs with the paclihas higher solubility in water than paclitaxel [19]. Third, taxel binding site of microtubules were studied. The
NATO Science for Peace and Security Series C: Environmental Security, 2009
The structural protein, β-tubulin is the target for a number of antimitotic compounds that bind to and inhibit microtubule dynamics, leading to apoptosis in all dividing cells. The existence of several isotypes of βtubulin, coupled with their varied distribution throughout different organisms provides a platform upon which to construct novel agents, which are able to differentiate between cell types. Several examples of compounds that perturb microtubule dynamics, such as paclitaxel, are currently some of the most effective drugs used in cancer chemotherapy. Additionally, MT disrupting agents such as the dinitroanilines, disrupt plant but not animal microtubules and are therefore useful herbicides. However, even with their wide use and important function, the method of action of MT disrupting compounds is unknown. We have performed homology modeling on approximately 500 α-and β-tubulin sequences and identified an expected global, structural similarity of tubulin monomers. We have been able to calculate discernable differences in several properties, including their net electric charge, volume, surface area, electric dipole moment and dipole vector orientation. These are properties that may influence the functional characteristics of individual tubulin monomers, thereby resulting in a global effect on microtubule stability and assembly kinetics.
A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs
Proceedings of the National Academy of Sciences of the United States of America, 2014
The recent success of antibody-drug conjugates (ADCs) in the treatment of cancer has led to a revived interest in microtubule-destabilizing agents. Here, we determined the high-resolution crystal structure of the complex between tubulin and maytansine, which is part of an ADC that is approved by the US Food and Drug Administration (FDA) for the treatment of advanced breast cancer. We found that the drug binds to a site on β-tubulin that is distinct from the vinca domain and that blocks the formation of longitudinal tubulin interactions in microtubules. We also solved crystal structures of tubulin in complex with both a variant of rhizoxin and the phase 1 drug PM060184. Consistent with biochemical and mutagenesis data, we found that the two compounds bound to the same site as maytansine and that the structures revealed a common pharmacophore for the three ligands. Our results delineate a distinct molecular mechanism of action for the inhibition of microtubule assembly by clinically r...
Arabian Journal of Chemistry, 2015
Microtubules are tube-shaped, filamentous and cytoskeletal proteins that are essential in all eukaryotic cells. Microtubule is an attractive and promising target for anticancer agents. In this study, three-dimensional quantitative structure activity relationships (3D-QSAR) including comparative molecular field analysis, CoMFA, and comparative molecular similarity indices analysis, CoMSIA, were performed on a set of 45 (E)-N-Aryl-2-ethene-sulfonamide analogues as microtubule-targeted anti-prostate cancer agents. Automated grid potential analysis, AutoGPA module in Molecular Operating Environment 2009.10 (MOE) as a new 3D-QSAR approach with the pharmacophore-based alignment was carried out on the same dataset. AutoGPA-based 3D-QSAR model yielded better prediction parameters than CoMFA and CoMSIA. Based on the contour maps generated from the models, some key features were identified in (E)-N-Aryl-2arylethene-sulfonamide analogues that were responsible for the anti-cancer activity. Virtual screening was performed based on pharmacophore modeling and molecular docking to identify the new inhibitors from ZINC database. Seven top ranked compounds were found based on Gold score fitness function. In silico ADMET studies were performed on compounds retrieved from virtual screening in compliance with the standard ranges.
Chemistry & Biology, 2005
The interactions of microtubules with most compounds described as stabilizing agents have been studied. Several of them (lonafarnib, dicumarol, lutein, and jatrophane polyesters) did not show any stabilizing effect on microtubules. Taccalonolides A and E show paclitaxel-like effects in cells, but they were not able to modulate in vitro tubulin assembly or to bind microtubules, which suggests that other factors are involved in their cellular effects. The binding constants of epothilones, eleutherobin, discodermolide, sarcodictyins, 3,17b-diacetoxy-2-ethoxy-6-oxo-B-homo-estra-1,3,5(10)triene, and dictyostatin to the paclitaxel site; the critical concentrations of ligand-induced assembly; and their cytotoxicity in carcinoma cells have been measured, and correlations between these parameters have been determined. The inhibition of cell proliferation correlates better with the binding enthalpy change than with the binding constants, suggesting that large, favorable enthalpic contribution to the binding is desired to design paclitaxel site drugs with higher cytotoxicity.