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A comparative analysis of protein targets of withdrawn cardiovascular drugs in human and mouse.

ABSTRACT: BACKGROUND:Mouse is widely used in animal testing of cardiovascular disease. However, a large number of cardiovascular drugs that have been experimentally proved to work well on mouse were withdrawn because they caused adverse side effects in human. METHODS:In this study, we investigate whether binding patterns of withdrawn cardiovascular drugs are conserved between mouse and human through computational dockings and molecular dynamic simulations. In addition, we also measured the level of conservation of gene expression patterns of the drug targets and their interacting partners by analyzing the microarray data. RESULTS:The results show that target proteins of withdrawn cardiovascular drugs are functionally conserved between human and mouse. However, all the binding patterns of withdrawn drugs we retrieved show striking difference due to sequence divergence in drug-binding pocket, mainly through loss or gain of hydrogen bond donors and distinct drug-binding pockets. The binding affinities of withdrawn drugs to their receptors tend to be reduced from mouse to human. In contrast, the FDA-approved and best-selling drugs are little affected. CONCLUSIONS:Our analysis suggests that sequence divergence in drug-binding pocket may be a reasonable explanation for the discrepancy of drug effects between animal models and human.

SUBMITTER: Zhao Y

PROVIDER: S-EPMC3413526 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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A comparative analysis of protein targets of withdrawn cardiovascular drugs in human and mouse.

Zhao Yuqi Y Wang Jingwen J Wang Yanjie Y Huang Jingfei J

Journal of clinical bioinformatics 20120501 1

<h4>Background</h4>Mouse is widely used in animal testing of cardiovascular disease. However, a large number of cardiovascular drugs that have been experimentally proved to work well on mouse were withdrawn because they caused adverse side effects in human.<h4>Methods</h4>In this study, we investigate whether binding patterns of withdrawn cardiovascular drugs are conserved between mouse and human through computational dockings and molecular dynamic simulations. In addition, we also measured the ...[more]

PMID: 22548699

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Project description:BACKGROUND: The availability of abundant sequence data from key model organisms has made large scale studies of molecular evolution an exciting possibility. Here we use full length cDNA alignments comprising more than 700,000 nucleotides from human, mouse, pig and the Japanese pufferfish Fugu rubrices in order to investigate 1) the relationships between three major lineages of mammals: rodents, artiodactyls and primates, and 2) the rate of evolution and the occurrence of positive Darwinian selection using codon based models of sequence evolution. RESULTS: We provide evidence that the evolutionary splits among primates, rodents and artiodactyls happened shortly after each other, with most gene trees favouring a topology with rodents as outgroup to primates and artiodactyls. Using an unrooted topology of the three mammalian species we show that since their diversification, the pig and mouse lineages have on average experienced 1.44 and 2.86 times as many synonymous substitutions as humans, respectively, whereas the rates of non-synonymous substitutions are more similar. The analysis shows the highest average dN/dS ratio in the human lineage, followed by the pig and then the mouse lineages. Using codon based models we detect signals of positive Darwinian selection in approximately 5.3%, 4.9% and 6.0% of the genes on the human, pig and mouse lineages respectively. Approximately 16.8% of all the genes studied here are not currently annotated as functional genes in humans. Our analyses indicate that a large fraction of these genes may have lost their function quite recently or may still be functional genes in some or all of the three mammalian species. CONCLUSIONS: We present a comparative analysis of protein coding genes from three major mammalian lineages. Our study demonstrates the usefulness of codon-based likelihood models in detecting selection and it illustrates the value of sequencing organisms at different phylogenetic distances for comparative studies.

Project description:In the Guidance for Industry from the Food and Drug Administration in 2008, excess cardiovascular risk should be ruled out in trials of all new antidiabetic drugs; however, relatively few studies have focused on cardiovascular safety with antidiabetic drug use. We aimed to examine mortality and cardiovascular risk using a network meta-analysis. We searched the Medline, Embase, Cochrane, and ClinicalTrials.gov registry databases in March 2016 to identify randomized controlled trials reporting cardiovascular risk with the following oral antidiabetic drugs: metformin, sulfonylureas, thiazolidinedione (TZD), dipeptidyl peptidase-4 (DPP4) inhibitors, and sodium-glucose co-transporter-2 (SGLT2) inhibitors. We assessed the differences in the risks of all-cause mortality, cardiovascular-related mortality, acute coronary syndrome (ACS), and myocardial infarction (MI) among antidiabetic drugs with fixed effect models for direct pairwise comparisons and Bayesian network meta-analyses to integrate direct and indirect comparisons. Of the 101,183 patients in 73 randomized controlled trials, 3,434 (3.4%) died. The relative risks of all-cause mortality with SGLT2 inhibitor use were 0.68 (95% credible interval: 0.57-0.80), 0.74 (0.49-1.10), 0.63 (0.46-0.87), 0.71 (0.55-0.90), and 0.65 (0.54-0.78), compared with placebo, metformin, sulfonylurea, TZD, and DPP4 inhibitor, respectively. The relative risks of cardiovascular-related mortality with SGLT2 inhibitor use were 0.61 (0.50-0.76), 0.81(0.36-1.90), 0.52(0.31-0.88), 0.66(0.49-0.91), and 0.61(0.48-0.77), compared with placebo, metformin, sulfonylurea, TZD, and DPP4 inhibitor, respectively. The relative risks of ACS with SGLT2 inhibitor use was consistent with that of all-cause mortality. SGLT2 inhibitor use was associated with a lower risk of ACS than the other OADs and placebo. The relative risks of MI with SGLT2 inhibitor use were 0.77 (0.63-0.93) and 0.75 (0.60-0.94), compared with placebo and DPP4 inhibitor, respectively. The currently available data provide the evidence of cardiovascular benefit from use of SGLT2 inhibitors to patients with type 2 diabetes, although additional results from ongoing studies will be pivotal.

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A comparative analysis of protein targets of withdrawn cardiovascular drugs in human and mouse.

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A comparative analysis of protein targets of withdrawn cardiovascular drugs in human and mouse.

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