A comparative analysis of protein targets of withdrawn cardiovascular drugs in human and mouse

BackgroundMouse 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 However, a large number of cardiovascular drugs that have been experimentally proved to work well on mouse were withdrawn because they caused adverse side effects in human.MethodsIn this study, we investigate whether binding patterns of withdrawn cardiovascular drugs are conserved between mouse and human through computational dockings and molecular dynamic simulations.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targets and their interacting partners by analyzing the microarray data.ResultsThe results show that target proteins of withdrawn cardiovascular drugs are functionally conserved between human and mouse. However, all the binding patterns of withdrawn drugs we retrieved show striking difference due to sequence divergence in drug-binding pocket, mainly through loss or gain of hydrogen bond donors and distinct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 The binding affinities of withdrawn drugs to their receptors tend to be reduced from mouse to human.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.ConclusionsOur 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.

[1]  Charles L. Brooks,et al.  Detailed analysis of grid‐based molecular docking: A case study of CDOCKER—A CHARMm‐based MD docking algorithm , 2003, J. Comput. Chem..

[2]  Jianzhi Zhang,et al.  Null mutations in human and mouse orthologs frequently result in different phenotypes , 2008, Proceedings of the National Academy of Sciences.

[3]  P. Shannon,et al.  Cytoscape: a software environment for integrated models of biomolecular interaction networks. , 2003, Genome research.

[4]  F. Musshoff,et al.  ILLEGAL OR LEGITIMATE USE? PRECURSOR COMPOUNDS TO AMPHETAMINE AND METHAMPHETAMINE , 2000, Drug metabolism reviews.

[5]  R. Iyengar,et al.  Systems approaches to polypharmacology and drug discovery. , 2010, Current opinion in drug discovery & development.

[6]  T. Blundell,et al.  Comparative protein modelling by satisfaction of spatial restraints. , 1993, Journal of molecular biology.

[7]  Monitoring technologies and genetic engineering are producing a growing array of animal models for psychiatric disorders , .

[8]  Alexander D. MacKerell,et al.  Importance of the CMAP correction to the CHARMM22 protein force field: dynamics of hen lysozyme. , 2006, Biophysical journal.

[9]  D. Gifford,et al.  Tissue-specific transcriptional regulation has diverged significantly between human and mouse , 2007, Nature Genetics.

[10]  Alexander D. MacKerell,et al.  Extending the treatment of backbone energetics in protein force fields: Limitations of gas‐phase quantum mechanics in reproducing protein conformational distributions in molecular dynamics simulations , 2004, J. Comput. Chem..

[11]  R. Shah,et al.  Can pharmacogenetics help rescue drugs withdrawn from the market? , 2006, Pharmacogenomics.

[12]  Chi-Wai Wong,et al.  Troglitazone is an estrogen-related receptor alpha and gamma inverse agonist. , 2010, Biochemical pharmacology.

[13]  Y. Zhang,et al.  IntAct—open source resource for molecular interaction data , 2006, Nucleic Acids Res..

[14]  Luca Testa,et al.  The direct thrombin inhibitor ximelagatran/melagatran: a systematic review on clinical applications and an evidence based assessment of risk benefit profile , 2007, Expert opinion on drug safety.

[15]  D E Roach,et al.  Decrease in density of INa is in the common final pathway to heart block in murine hearts overexpressing calcineurin. , 2006, American journal of physiology. Heart and circulatory physiology.

[16]  Elie Dolgin,et al.  Animal testing alternatives come alive in US , 2010, Nature Medicine.

[17]  Greg Miller,et al.  Pharmacology. The puzzling rise and fall of a dark-horse Alzheimer's drug. , 2010, Science.

[18]  P. Benfey,et al.  From Genotype to Phenotype: Systems Biology Meets Natural Variation , 2008, Science.

[19]  W. L. Jorgensen,et al.  Comparison of simple potential functions for simulating liquid water , 1983 .

[20]  J. Deisenhofer,et al.  Crystal structure of the catalytic portion of human HMG‐CoA reductase: insights into regulation of activity and catalysis , 2000, The EMBO journal.

[21]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[22]  Ian M. Donaldson,et al.  The Biomolecular Interaction Network Database and related tools 2005 update , 2004, Nucleic Acids Res..

[23]  P Stieglitz,et al.  Malignant-hyperthermia susceptibility is associated with a mutation of the alpha 1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle. , 1997, American journal of human genetics.

[24]  Derek M. Yellon,et al.  Mibefradil, a T-Type and L-Type Calcium Channel Blocker, Limits Infarct Size through a Glibenclamide-Sensitive Mechanism , 1999, Cardiovascular Drugs and Therapy.

[25]  F. Blasi,et al.  Plasminogen activator inhibitor type‐1 : reactive center and amino‐terminal heterogeneity determined by protein and cDNA sequencing , 1986, FEBS letters.

[26]  Gabriele Ausiello,et al.  MINT: the Molecular INTeraction database , 2006, Nucleic Acids Res..

[27]  S. Bergmann,et al.  The evolution of gene expression levels in mammalian organs , 2011, Nature.

[28]  Ioannis Xenarios,et al.  DIP: The Database of Interacting Proteins: 2001 update , 2001, Nucleic Acids Res..

[29]  Frank T Peters,et al.  Amphetamine concentrations in human urine following single-dose administration of the calcium antagonist prenylamine-studies using fluorescence polarization immunoassay (FPIA) and GC-MS. , 2003, Journal of analytical toxicology.

[30]  J. Zou,et al.  Effect of mutation K85R on GSK-3beta: Molecular dynamics simulation. , 2008, Biochemical and biophysical research communications.

[31]  Benjamin A. Shoemaker,et al.  Deciphering Protein–Protein Interactions. Part II. Computational Methods to Predict Protein and Domain Interaction Partners , 2007, PLoS Comput. Biol..

[32]  David S. Wishart,et al.  DrugBank: a knowledgebase for drugs, drug actions and drug targets , 2007, Nucleic Acids Res..

[33]  Jingfei Huang,et al.  A systematic analysis of heart transcriptome highlights divergent cardiovascular disease pathways between animal models and humans. , 2012, Molecular bioSystems.

[34]  Z Mishal,et al.  Cerivastatin, an Inhibitor of HMG-CoA Reductase, Inhibits Urokinase/Urokinase-receptor Expression and MMP-9 Secretion by Peripheral Blood Monocytes , 2000, Thrombosis and Haemostasis.

[35]  Adam J. Smith,et al.  The Database of Interacting Proteins: 2004 update , 2004, Nucleic Acids Res..

[36]  Alicia Oshlack,et al.  Gene Regulation in Primates Evolves under Tissue-Specific Selection Pressures , 2008, PLoS genetics.

[37]  Julian Tirado-Rives,et al.  Contribution of conformer focusing to the uncertainty in predicting free energies for protein-ligand binding. , 2006, Journal of medicinal chemistry.

[38]  Hao Fan,et al.  Refinement of homology‐based protein structures by molecular dynamics simulation techniques , 2004, Protein science : a publication of the Protein Society.

[39]  Mike Tyers,et al.  BioGRID: a general repository for interaction datasets , 2005, Nucleic Acids Res..

[40]  A Sali,et al.  Comparative protein modeling by satisfaction of spatial restraints. , 1996, Molecular medicine today.

[41]  Wei Zhao,et al.  Preclinical study of dimebon on β-amyloid-mediated neuropathology in Alzheimer's disease , 2011, Molecular Neurodegeneration.

[42]  Tim J. P. Hubbard,et al.  SCOP database in 2004: refinements integrate structure and sequence family data , 2004, Nucleic Acids Res..

[43]  Michael Krams,et al.  Missing Steps in the STAIR Case: A Translational Medicine Perspective on the Development of NXY-059 for Treatment of Acute Ischemic Stroke , 2008, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[44]  Lisa Yan,et al.  Fully Automated Molecular Mechanics Based Induced Fit Protein-Ligand Docking Method , 2008, J. Chem. Inf. Model..

[45]  S. Horvath,et al.  Divergence of human and mouse brain transcriptome highlights Alzheimer disease pathways , 2010, Proceedings of the National Academy of Sciences.

[46]  Natalie Wilson,et al.  Human Protein Reference Database , 2004, Nature Reviews Molecular Cell Biology.

[47]  Andrej ⩽ali,et al.  Comparative protein modeling by satisfaction of spatial restraints , 1995 .

[48]  A. Aljada,et al.  Nuclear Factor-κB Suppressive and Inhibitor-κB Stimulatory Effects of Troglitazone in Obese Patients with Type 2 Diabetes: Evidence of an Antiinflammatory Action?1 , 2001 .

[49]  Stefan W Krause,et al.  Species-specific Regulation of Toll-like Receptor 3 Genes in Men and Mice* , 2003, Journal of Biological Chemistry.

[50]  A. Hopkins,et al.  The druggable genome , 2002, Nature Reviews Drug Discovery.

[51]  John T Cody,et al.  Precursor Medications as a Source of Methamphetamine and/or Amphetamine Positive Drug Testing Results , 2002, Journal of occupational and environmental medicine.

[52]  Paul Pavlidis,et al.  Activation of MAPK pathways links LMNA mutations to cardiomyopathy in Emery-Dreifuss muscular dystrophy. , 2007, The Journal of clinical investigation.

[53]  A. Aljada,et al.  Nuclear factor-kappaB suppressive and inhibitor-kappaB stimulatory effects of troglitazone in obese patients with type 2 diabetes: evidence of an antiinflammatory action? , 2001, The Journal of clinical endocrinology and metabolism.

[54]  Gong-Hua Li,et al.  CMASA: an accurate algorithm for detecting local protein structural similarity and its application to enzyme catalytic site annotation , 2010, BMC Bioinformatics.

[55]  Klaus Schulten,et al.  Molecular Dynamics Simulations Suggest that Electrostatic Funnel Directs Binding of Tamiflu to Influenza N1 Neuraminidases , 2010, PLoS Comput. Biol..