Structural And Chemical Basis For Anticancer Activity Of A Series Of β-tubulin Ligands: Molecular Modeling And 3d Qsar Studies

An important approach to cancer therapy is the design of small molecule modulators that interfere with microtubule dynamics through their specific binding to the β-subunit of tubulin. In the present work, comparative molecular field analysis (CoMFA) studies were conducted on a series of discodermolide analogs with antimitotic properties. Significant correlation coefficients were obtained (CoMFA(i), q2 = 0.68, r2 = 0.94; CoMFA(ii), q2 = 0.63, r2 = 0.91), indicating the good internal and external consistency of the models generated using two independent structural alignment strategies. The models were externally validated employing a test set, and the predicted values were in good agreement with the experimental results. The final QSAR models and the 3D contour maps provided important insights into the chemical and structural basis involved in the molecular recognition process of this family of discodermolide analogs, and should be useful for the design of new specific β-tubulin modulators with potent anticancer activity. ©2009 Sociedade Brasileira de Química.204693703Wittmann, T., Hyman, A., Desai, A., (2001) Nat. Cell. Biol., 3, pp. E28Jordan, M.A., Wilson, L., (2004) Nat. Ver. Cancer, 4, p. 253Hadfield, J.A., Ducki, S., Hirst, N., McGown, A.T., (2003) Prog. Cell Cycle Res., 5, p. 309Pellegrini, F., Budman, D.R., (2005) Cancer Invest, 23, p. 264Islam, M.N., Iskander, M.N., (2004) Mini Rev. Med. Chem., 4, p. 1077Snyder, J.P., (2007) Nat. Chem. Biol., 3, p. 81Schiff, P.B., Fant, J., Horwitz, S.B., (1979) Nature, 277, p. 665Rowinsky, E.K., (1997) Annu. Rev. Med., 48, p. 353Jordan, M.A., Toso, R.J., Thrower, D., Wilson, L., (1993) Proc. Natl. Acad. Sci. U. S. 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Fragment-based Qsar And Molecular Modeling Studies On A Series Of Discodermolide Analogs As Microtubule-stabilizing Anticancer Agents

Inhibition of microtubule function is an attractive rational approach to anticancer therapy. Although taxanes are the most prominent among the microtubule-stabilizers, their clinical toxicity, poor pharmacokinetic properties, and resistance have stimulated the search for new antitumor agents having the same mechanism of action. Discodermolide is an example of nontaxane natural product that has the same mechanism of action, demonstrating superior antitumor efficacy and therapeutic index. The extraordinary chemical and biological properties have qualified discodermolide as a lead structure for the design of novel anticancer agents with optimized therapeutic properties. In the present work, we have employed a specialized fragment-based method to develop robust quantitative structure - activity relationship models for a series of synthetic discodermolide analogs. 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A historicidade das teorias interpretativas do processo saúde-doença The historicity of the health-illness process interpretative theories

As diferentes teorias interpretativas do processo saúde-doença identificáveis ao longo da história têm como decorrência distintos projetos de intervenção sobre a realidade, em resposta a necessidades sociais. Até o século XIX, tais teorias podem ser sintetizadas nas vertentes ontológica e dinâmica. Na concepção ontológica, a doença assume o caráter de uma entidade natural ou sobrenatural, externa ao corpo humano, que se manifesta ao invadi-lo. A concepção dinâmica vê a doença como produto da desarmonia entre forças vitais, sendo que o restabelecimento da saúde advém da restauração do equilíbrio Ao final do século XVIII, predominavam na Europa como forma de explicação para o adoecimento humano os paradigmas sócio-ambientais, vinculados à concepção dinâmica, tendo se esboçado as primeiras evidências da determinação social do processo saúde-doença. Com o advento da Bacteriologia, a concepção ontológica firmou-se vitoriosa e suas conquistas levaram ao abandono dos critérios sociais na formulação e no enfrentamento dos problemas de saúde das populações. Na atualidade, identifica-se o predomínio da multicausalidade, com ênfase nos condicionantes individuais. Como alternativa para a sua superação, propõe-se a articulação das dimensões individual e coletiva do processo saúde-doença, em consonância com a Teoria da Intervenção Práxica de Enfermagem em Saúde Coletiva.<br>The interpretative theories of the health-illness process that can be identified through History have as consequence intervention projects upon the reality, in response to social needs. Until the 19 century, they could be synthesized in two main streams: ontologic and dynamic. In the ontologic conception, illness assumes the character of a natural or supernatural entity, external to the human body, that shows itself when invading it. The dynamic conception sees illness as a product of the disharmony among vital forces, and the re-establishment of the health comes of the restoration of this balance. At the end of the 18 century, the social-environmental paradigms prevailed in Europe as forms of explanation for human illness, linked to the dynamic conception, and the first evidences of the social determination of the health-illness process were formulated. The onset of the Bacteriologic Era made the ontologic conception victorious and its conquests led to the abandon of the social approaches to face the populations health problems. At the present time, one can identify the prevalence of the multicausal theory, with emphasis in the individual conditionings. This paper proposes the articulation of the individual and collective dimensions of the health-illness process, in consonance with the Theory of Nursing Praxical Intervention in Collective Health