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Drug target mining and analysis of the Chinese tree shrew for pharmacological testing.

Zhao F, Guo X, Wang Y, Liu J, Lee WH, Zhang Y - PLoS ONE (2014)

Bottom Line: The discovery of new drugs requires the development of improved animal models for drug testing.The Chinese tree shrew is considered to be a realistic candidate model.Target validation also demonstrated that the constitutive expression of the proteinase-activated receptors of tree shrew platelets is similar to that of human platelets but differs from that of mouse platelets.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, PR China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, PR China.

ABSTRACT
The discovery of new drugs requires the development of improved animal models for drug testing. The Chinese tree shrew is considered to be a realistic candidate model. To assess the potential of the Chinese tree shrew for pharmacological testing, we performed drug target prediction and analysis on genomic and transcriptomic scales. Using our pipeline, 3,482 proteins were predicted to be drug targets. Of these predicted targets, 446 and 1,049 proteins with the highest rank and total scores, respectively, included homologs of targets for cancer chemotherapy, depression, age-related decline and cardiovascular disease. Based on comparative analyses, more than half of drug target proteins identified from the tree shrew genome were shown to be higher similarity to human targets than in the mouse. Target validation also demonstrated that the constitutive expression of the proteinase-activated receptors of tree shrew platelets is similar to that of human platelets but differs from that of mouse platelets. We developed an effective pipeline and search strategy for drug target prediction and the evaluation of model-based target identification for drug testing. This work provides useful information for future studies of the Chinese tree shrew as a source of novel targets for drug discovery research.

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Top 20 drug targets ranked by weighted profiles.(A) Top 20 drug targets ranked by total score. FPKM values of each drug target in seven tissues represent its expression level in each tissue. (B) Top 20 drug targets ranked by drug score. Expression scores were not used to calculate drug scores.
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pone-0104191-g003: Top 20 drug targets ranked by weighted profiles.(A) Top 20 drug targets ranked by total score. FPKM values of each drug target in seven tissues represent its expression level in each tissue. (B) Top 20 drug targets ranked by drug score. Expression scores were not used to calculate drug scores.

Mentions: To determine whether total score ranking is an appropriate indicator of candidate drug target quality, we compared drug scores and total scores between the top 20 drug targets. High total scores were associated with drug targets having high expression in tissues, particularly in the liver and kidneys (Figure 3A). Unlike the total scores, expression patterns were considered when calculating the drug score of each drug target. Our comparative analysis revealed that half of the drug targets with high drug scores were expressed at low levels in tissues (Figure 3B). Total scores accurately reflected the quality of all potential drug targets, indicating that target drug expression is an important predictor of drug quality. Based on the total score, the top 20 tree shrew drug targets (Table 2) included several homologs of targets for cancer chemotherapy, including vascular endothelial growth factor receptor 2 (VEGFR2), membrane metallo-endopeptidase (MME), and the proto-oncogene tyrosine-protein kinase Yes (YES1). In addition, as expected, several targets (NR3C1, GSK3B, EGM_09788) with high scores were related to depression and age-related decline. This result is consistent with the report of Fuchs [7].


Drug target mining and analysis of the Chinese tree shrew for pharmacological testing.

Zhao F, Guo X, Wang Y, Liu J, Lee WH, Zhang Y - PLoS ONE (2014)

Top 20 drug targets ranked by weighted profiles.(A) Top 20 drug targets ranked by total score. FPKM values of each drug target in seven tissues represent its expression level in each tissue. (B) Top 20 drug targets ranked by drug score. Expression scores were not used to calculate drug scores.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126716&req=5

pone-0104191-g003: Top 20 drug targets ranked by weighted profiles.(A) Top 20 drug targets ranked by total score. FPKM values of each drug target in seven tissues represent its expression level in each tissue. (B) Top 20 drug targets ranked by drug score. Expression scores were not used to calculate drug scores.
Mentions: To determine whether total score ranking is an appropriate indicator of candidate drug target quality, we compared drug scores and total scores between the top 20 drug targets. High total scores were associated with drug targets having high expression in tissues, particularly in the liver and kidneys (Figure 3A). Unlike the total scores, expression patterns were considered when calculating the drug score of each drug target. Our comparative analysis revealed that half of the drug targets with high drug scores were expressed at low levels in tissues (Figure 3B). Total scores accurately reflected the quality of all potential drug targets, indicating that target drug expression is an important predictor of drug quality. Based on the total score, the top 20 tree shrew drug targets (Table 2) included several homologs of targets for cancer chemotherapy, including vascular endothelial growth factor receptor 2 (VEGFR2), membrane metallo-endopeptidase (MME), and the proto-oncogene tyrosine-protein kinase Yes (YES1). In addition, as expected, several targets (NR3C1, GSK3B, EGM_09788) with high scores were related to depression and age-related decline. This result is consistent with the report of Fuchs [7].

Bottom Line: The discovery of new drugs requires the development of improved animal models for drug testing.The Chinese tree shrew is considered to be a realistic candidate model.Target validation also demonstrated that the constitutive expression of the proteinase-activated receptors of tree shrew platelets is similar to that of human platelets but differs from that of mouse platelets.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, PR China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, PR China.

ABSTRACT
The discovery of new drugs requires the development of improved animal models for drug testing. The Chinese tree shrew is considered to be a realistic candidate model. To assess the potential of the Chinese tree shrew for pharmacological testing, we performed drug target prediction and analysis on genomic and transcriptomic scales. Using our pipeline, 3,482 proteins were predicted to be drug targets. Of these predicted targets, 446 and 1,049 proteins with the highest rank and total scores, respectively, included homologs of targets for cancer chemotherapy, depression, age-related decline and cardiovascular disease. Based on comparative analyses, more than half of drug target proteins identified from the tree shrew genome were shown to be higher similarity to human targets than in the mouse. Target validation also demonstrated that the constitutive expression of the proteinase-activated receptors of tree shrew platelets is similar to that of human platelets but differs from that of mouse platelets. We developed an effective pipeline and search strategy for drug target prediction and the evaluation of model-based target identification for drug testing. This work provides useful information for future studies of the Chinese tree shrew as a source of novel targets for drug discovery research.

Show MeSH
Related in: MedlinePlus