Structure- Activity Relationships (SAR) - ppt download
Clarke DA, Elion GB, HITCHINGS GH, STOCK CC. Structure-activity relationships among purines related to 6-mercaptopurine. Cancer Res. ;18(4) Mercaptopurine (6-MP), sold under the brand name Purinethol among others, is a medication . Indeed, testing for TPMT activity is currently one of the few examples of pharmacogenetics being translated into . "Possible carcinogenic effect of 6-mercaptopurine on bone marrow stem cells: relation to thiopurine metabolism". We built a structure-activity relationship (SAR) model for evaluating hepatotoxicity . For example liver steatosis is caused by abnormal synthesis and elimination .. Methotrexate is a methyl analog of folic acid, used in the treatment of various.
Several published studies have demonstrated that the use of allopurinol in combination with low dose 6-MP helps reduce 6-MP levels, which are toxic to liver tissue, whilst increasing the therapeutic levels of 6-MP for some inflammatory conditions.
Mechanisms of action[ edit ] This section may be too technical for most readers to understand. Please help improve it to make it understandable to non-expertswithout removing the technical details. December Learn how and when to remove this template message Official information from the package insert for purinethol: Both TIMP and MTIMP have been reported to inhibit glutaminephosphoribosylpyrophosphate amidotransferase, the first enzyme unique to the de novo pathway for purine ribonucleotide synthesis.
Experiments indicate that radiolabeled mercaptopurine may be recovered from the DNA in the form of deoxythioguanosine.
Animal tumors that are resistant to mercaptopurine often have lost the ability to convert mercaptopurine to TIMP. However, it is clear that resistance to mercaptopurine may be acquired by other means as well, particularly in human leukemias.
It is not known exactly which of any one or more of the biochemical effects of mercaptopurine and its metabolites are directly or predominantly responsible for cell death. Since this enzyme is the rate limiting factor for purine synthesis,  this alters the synthesis and function of RNA and DNA. Pharmacogenetics[ edit ] The enzyme thiopurine S-methyltransferase TPMT is responsible, in part, for the inactivation of 6-mercaptopurine.
TPMT catalyzes the methylation of 6-mercaptopurine into the inactive metabolite 6-methylmercaptopurine — this methylation prevents mercaptopurine from further conversion into active, cytotoxic thioguanine nucleotide TGN metabolites. Elion and George H. Rhoads who had run chemical weapons programs for the US army and had been involved in the work that led to the discovery that nitrogen mustards could potentially be used as cancer drugs, and had become the director of Memorial in Figure 2 shows the decision tree we applied for building the model for the prediction of hepatotoxicity.
If more than one SAs is found, the prediction depends on the number of SAs: Since it is preferable to overestimate hepatotoxicity rather than not to recognize unsafe compounds, the overall model's architecture followed a conservative approach.
Decision tree developed for the hepatotoxicity model. Percentages of correctly predicted, wrongly predicted and non-predicted unknown compounds in the training, test and external validation sets.
Performance of the model in the training, test and external validation sets. Out of compounds that were present in the training set, were not predicted by the model unknown, non-predicted. For 91 compounds in the test set molecules the model did not provide any prediction unknown, non-predicted48 compounds were correctly identified as hepatotoxic TP and 15 as non-hepatotoxic TN.
The number of experimentally negative non-hepatotoxic compounds wrongly predicted as hepatotoxic FP was 30 and the number of positive compounds hepatotoxic wrongly predicted as negative FN was 6.
Mercaptopurine - Wikipedia
In the external validation set compounds59 chemicals were not predicted by the model unknown, non-predictedthe numbers of TP and TN was 35 and 5 respectively. Figure 3 shows percentages of correctly predicted and wrongly predicted compounds in the training, test and external validation sets.
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- Structure- Activity Relationships (SAR)
- Structure-activity relationships among purines related to 6-mercaptopurine.
Discussion Limitations and Weaknesses of Experimental Hepatotoxicity Data High-quality and reliable biological data are essential in order to build predictive models to provide relevant information about the toxicological behavior of a substance. Ideally the data for building a model should be obtained using a unique, well-standardized protocol, in the same laboratory by the same scientists.
It is also important that these data refer to a clear and unambiguous endpoint Cronin and Schultz, However, this is difficult, especially for hepatotoxicity, since the data are spread out in the literature and databases, refer to several endpoints related to hepatotoxicity steatosis, colestasis, fibrosis etc.
Then, as previously mentioned, there is no a good single standard indicator of DILI with high sensitivity and specificity Przybylak and Cronin, Indeed, no well-defined biomarkers exist for the identification of hepatotoxicity in vitro or in vivo. Consequently, the data in the literature refer to different effects and mechanisms of action underlying the endpoint of hepatotoxicity.
This data set, compiled using the data mining procedure, suffers some limitations. Firstly it does not make any distinction between idiosyncratic and dose-dependent toxicity. Idiosyncratic toxicity refers to an abnormal reaction to a drug that is not connected to its pharmacological activity but is due to individual hypersensitivity Cheng and Dixon, ; Russmann et al. This toxicity does not follow any specific mode of action, but the adverse reactions to drugs are of unknown etiology and involved only a small proportion of the population Walgren et al.
This means that where information is lacking it has been assumed that the compound was negative.
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Even if it is true that for well-known and investigated drugs, the lack of information can be taken as negative Hewitt et al. When the hepatocyte membrane is damaged these enzymes, which are normally located in the cytosol, are released into the bloodstream Pari and Murugan, Although the serum transaminases are commonly used as indicators of liver injury and reflect damage to hepatocytes Ozer et al.
For example, ALT and AST are present in other tissues heart, brain and skeletal muscle besides the liver and so they are released into the circulation when there is damage to these tissues. AST mostly increases in case of myocyte damage due to extreme physical effort Ozer et al. LDH is another enzyme occasionally used as a biomarker of hepatocellular injury.
However, it is not routinely employed since its specificity is questionable Ramaiah, More recently genomics, proteomics and metabolomics have been proposed as valuable techniques for discovering biomarkers Amacher et al. However, the most of the datasets is not suitable to be used alone for classification modeling.SAR of phenylethanolamine /SAR of sympathomimetics
In conclusion, the data we used for modeling have a certain level of uncertainty due to these points which may have influenced the reliability and performance of the model. An alternative that could limit the uncertainty linked to hepatotoxicity data is to use in vitro data obtained if possible on the same cell lines and using the same laboratory assay and conditions.
However, not much public data is available in the open literature for this purpose and this approach too suffers some limitations such as the influence of genetic and environmental factors in the variations of biochemistry Przybylak and Cronin, Mechanistic Explanation of SAs We propose, when possible, a mechanistic rationale using the information in the literature and in public databases PubChem https: N-Containing Heterocyclic Aromatic Compounds: Pyridine, Pyrazine, Pyrimidine This SA, identified by the ID number 1 Table 1is a generic chemical structure that may be seen in several different chemical families.
In the training set it matches 57 compounds covering different chemical and therapeutic classes41 of them classified as hepatotoxic.
Considering the lack of specificity of this SA, it is impossible to highlight any single mechanism of action that may explain the toxicity. In the training set this chemical fragment correctly identified hepatotoxic compounds in However, we identified two sub-families in this large group of drugs.