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Development of a less toxic dichloroacetate analogue by docking and descriptor analysis

By Kannan Subramanian and Anand S Ramaian

Abstract

Dichloroacetate (DCA) is a synthetic compound that promotes the activity of pyruvate dehydrogenase (PDH) by inhibiting its repressor protein called pyruvate dehydrogenase kinase (PDHK). The activation of PDH leads to a reduction in ambient cellular lactate concentrations both in vitro and in vivo which contributes to the therapeutic use of DCA in the treatment of systemic lactic acidosis in humans. The therapeutic potential of DCA is now being explored in disorders that are accompanied by elevations of lactate concentration such as in hypoxic cancer cells. Yet conflicting evidence regarding its mutagenic potential has been a major setback in its clinical trials. Hence, docking and descriptor analysis of halogen substituted DCA analogues were performed to find out a drug candidate with less toxicity and better binding affinity than DCA. The Docking analysis was carried out using human PDHK isozyme 2, the physiological receptor for DCA. Bromo(iodo)acetate and Diiodoacetate were found out to be the plausible analogues of DCA from this study

Topics: Hypothesis
Publisher: Biomedical Informatics
OAI identifier: oai:pubmedcentral.nih.gov:3039993
Provided by: PubMed Central

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Citations

  1. (2007). 46: 251 [PMID:17497074] Edited by P. Kangueane Citation: Subramanian et al,
  2. (2004). Aalten Acta Crystallographica
  3. (2007). Cancer Cell
  4. (2002). CB Thompson Trends Endocrinol Metab
  5. (2004). Nat Rev Cancer
  6. (2006). Neurology
  7. (1956). Science
  8. (2005). Trends Biochem Sci