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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
MeSH Review

Drug Design

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Disease relevance of Drug Design


Psychiatry related information on Drug Design


High impact information on Drug Design

  • Because the Id genes are expressed at very low levels in adults, they make attractive new targets for anti-angiogenic drug design [8].
  • Thus, benzodiazepine-induced behavioural responses are mediated by specific GABA(A) receptor subtypes in distinct neuronal circuits, which is of interest for drug design [9].
  • Atomic structure of thymidylate synthase: target for rational drug design [10].
  • This PPAR-gamma-dependent anti-inflammatory mechanism defines new cellular targets for therapeutic drug design and interventions for the treatment of chronic inflammation [11].
  • The details of the structure lead to a model for the mechanism of UL42, provide the basis for drug design, and allow modeling of other proteins that lack sequence homology with UL42 or PCNA [12].

Chemical compound and disease context of Drug Design


Biological context of Drug Design


Anatomical context of Drug Design

  • The structure enables modelling of the docking interactions to its ligands, for example from focal adhesion kinase, and supports structure-based drug design of inhibitors of the CAS-FAK interaction [23].
  • Abnormally high human neutrophil elastase (HNE) levels are involved in several diseases; therefore, inhibitors of HNE are of interest as targets for drug design [24].
  • It is interesting to find that P8 and P9 peptides inhibited syncytia formation, suggesting that the P8 and P9 spanning regions may provide a good target for anti-SARS-CoV drug design [25].
  • PNP is therefore a target for inhibitor development aiming at T-cell immune response modulation and has been submitted to extensive structure-based drug design [26].
  • Previous reports from this laboratory have shown marked cytocidal effects of the ISIS-3466 antisense phosphorothioate oligodeoxynucleotide to the human nucleolar protein p120 on human cancer cell lines in vitro and inhibition of tumor growth in vivo in an i.p/i.p. LOX cell model (L. Perlaky et al. Anti-Cancer Drug Design 8:3-14, 1993) [27].

Associations of Drug Design with chemical compounds

  • Using a structure-based drug design approach ortho-trifluormethylphenyl anthranilic acid and N-(meta-trifluoromethylphenyl) phenoxazine 4, 6-dicarboxylic acid have been discovered to be very potent and specific TTR fibril formation inhibitors [28].
  • Crystal structure of human type II inosine monophosphate dehydrogenase: implications for ligand binding and drug design [29].
  • Inhibitors combining guanidinium-like structural motifs with long chains specifically targeting this residue are good candidates for rational isoform-specific drug design [30].
  • This trypanothione-dependent glyoxalase I is therefore an attractive focus for additional biochemical and genetic investigation as a possible target for rational drug design [31].
  • The generation of eicosanoids (prostaglandins, leukotrienes, and lipoxins), oxygenated lipids, and PAF remain the focus of rational drug design targets given their established roles in cell-cell communication and as mediators in inflammation and pathophysiologic events [32].

Gene context of Drug Design

  • The perforin/granzyme pathway may therefore represent a novel target for anti-GvHD drug design [33].
  • The susceptibility differences to RR inhibitors between p53R2 and hRRM2 may lead to a new direction in drug design for human cancer treatment [34].
  • Reconstitution of p16 function in transformed cells is therefore an attractive target for anti-cancer drug design [35].
  • Altogether, we have identified a minimal peptide that inhibits Stat3 signaling and provides the conceptual basis for use of this peptide as a lead for novel peptidomimetic drug design [36].
  • Based on this study, we propose a model for a complex with the RARgamma-specific agonist CD666 that shows the possible applications for structure-based drug design of RAR isotype-selective retinoids [37].

Analytical, diagnostic and therapeutic context of Drug Design


  1. Blimp-1 is required for maintenance of long-lived plasma cells in the bone marrow. Shapiro-Shelef, M., Lin, K.I., Savitsky, D., Liao, J., Calame, K. J. Exp. Med. (2005) [Pubmed]
  2. Crystal structures of Toxoplasma gondii uracil phosphoribosyltransferase reveal the atomic basis of pyrimidine discrimination and prodrug binding. Schumacher, M.A., Carter, D., Scott, D.M., Roos, D.S., Ullman, B., Brennan, R.G. EMBO J. (1998) [Pubmed]
  3. Targeting HIV-1 protease: a test of drug-design methodologies. West, M.L., Fairlie, D.P. Trends Pharmacol. Sci. (1995) [Pubmed]
  4. From nonpeptide toward noncarbon protease inhibitors: metallacarboranes as specific and potent inhibitors of HIV protease. Cígler, P., Kozísek, M., Rezácová, P., Brynda, J., Otwinowski, Z., Pokorná, J., Plesek, J., Grüner, B., Dolecková-Maresová, L., Mása, M., Sedlácek, J., Bodem, J., Kräusslich, H.G., Král, V., Konvalinka, J. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  5. Modulation of atrioventricular nodal function by metabolic and allosteric regulators of endogenous adenosine in guinea pig heart. Dennis, D.M., Raatikainen, M.J., Martens, J.R., Belardinelli, L. Circulation (1996) [Pubmed]
  6. Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor. Hong, L., Koelsch, G., Lin, X., Wu, S., Terzyan, S., Ghosh, A.K., Zhang, X.C., Tang, J. Science (2000) [Pubmed]
  7. Efficacy of methylphenidate and behavioral intervention on classroom behavior in children with ADHD and mental retardation. Johnson, C.R., Handen, B.L., Lubetsky, M.J., Sacco, K.A. Behavior modification. (1994) [Pubmed]
  8. Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts. Lyden, D., Young, A.Z., Zagzag, D., Yan, W., Gerald, W., O'Reilly, R., Bader, B.L., Hynes, R.O., Zhuang, Y., Manova, K., Benezra, R. Nature (1999) [Pubmed]
  9. Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes. Rudolph, U., Crestani, F., Benke, D., Brünig, I., Benson, J.A., Fritschy, J.M., Martin, J.R., Bluethmann, H., Möhler, H. Nature (1999) [Pubmed]
  10. Atomic structure of thymidylate synthase: target for rational drug design. Hardy, L.W., Finer-Moore, J.S., Montfort, W.R., Jones, M.O., Santi, D.V., Stroud, R.M. Science (1987) [Pubmed]
  11. Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-gamma and RelA. Kelly, D., Campbell, J.I., King, T.P., Grant, G., Jansson, E.A., Coutts, A.G., Pettersson, S., Conway, S. Nat. Immunol. (2004) [Pubmed]
  12. The crystal structure of an unusual processivity factor, herpes simplex virus UL42, bound to the C terminus of its cognate polymerase. Zuccola, H.J., Filman, D.J., Coen, D.M., Hogle, J.M. Mol. Cell (2000) [Pubmed]
  13. Diospyrin, a bisnaphthoquinone: a novel inhibitor of type I DNA topoisomerase of Leishmania donovani. Ray, S., Hazra, B., Mittra, B., Das, A., Majumder, H.K. Mol. Pharmacol. (1998) [Pubmed]
  14. Synthesis and antiviral properties of (+/-)-5'-noraristeromycin and related purine carbocyclic nucleosides. A new lead for anti-human cytomegalovirus agent design. Patil, S.D., Schneller, S.W., Hosoya, M., Snoeck, R., Andrei, G., Balzarini, J., De Clercq, E. J. Med. Chem. (1992) [Pubmed]
  15. Comparison of the anti-influenza virus activity of RWJ-270201 with those of oseltamivir and zanamivir. Bantia, S., Parker, C.D., Ananth, S.L., Horn, L.L., Andries, K., Chand, P., Kotian, P.L., Dehghani, A., El-Kattan, Y., Lin, T., Hutchison, T.L., Montgomery, J.A., Kellog, D.L., Babu, Y.S. Antimicrob. Agents Chemother. (2001) [Pubmed]
  16. 'Tomudex' (ZD1694): a novel thymidylate synthase inhibitor with clinical antitumour activity in a range of solid tumours. 'Tomudex' International Study Group. Cunningham, D., Zalcberg, J., Smith, I., Gore, M., Pazdur, R., Burris, H., Meropol, N.J., Kennealey, G., Seymour, L. Ann. Oncol. (1996) [Pubmed]
  17. Antiestrogenic piperidinediones designed prospectively using computer graphics and energy calculations of DNA-ligand complexes. Hendry, L.B., Chu, C.K., Copland, J.A., Mahesh, V.B. J. Steroid Biochem. Mol. Biol. (1994) [Pubmed]
  18. Purified photoproducts of merocyanine 540 trigger cytochrome C release and caspase 8-dependent apoptosis in human leukemia and melanoma cells. Pervaiz, S., Seyed, M.A., Hirpara, J.L., Clément, M.V., Loh, K.W. Blood (1999) [Pubmed]
  19. Active site of trypanothione reductase. A target for rational drug design. Hunter, W.N., Bailey, S., Habash, J., Harrop, S.J., Helliwell, J.R., Aboagye-Kwarteng, T., Smith, K., Fairlamb, A.H. J. Mol. Biol. (1992) [Pubmed]
  20. Mechanistic studies comparing the incorporation of (+) and (-) isomers of 3TCTP by HIV-1 reverse transcriptase. Feng, J.Y., Anderson, K.S. Biochemistry (1999) [Pubmed]
  21. Kukoamine A and other hydrophobic acylpolyamines: potent and selective inhibitors of Crithidia fasciculata trypanothione reductase. Ponasik, J.A., Strickland, C., Faerman, C., Savvides, S., Karplus, P.A., Ganem, B. Biochem. J. (1995) [Pubmed]
  22. Dimerization of G-protein-coupled receptors: implications for drug design and signaling. Tallman, J. Neuropsychopharmacology (2000) [Pubmed]
  23. The 1.1 A resolution crystal structure of the p130cas SH3 domain and ramifications for ligand selectivity. Wisniewska, M., Bossenmaier, B., Georges, G., Hesse, F., Dangl, M., Künkele, K.P., Ioannidis, I., Huber, R., Engh, R.A. J. Mol. Biol. (2005) [Pubmed]
  24. A multistep approach to structure-based drug design: studying ligand binding at the human neutrophil elastase. Steinbrecher, T., Case, D.A., Labahn, A. J. Med. Chem. (2006) [Pubmed]
  25. Synthetic peptides derived from SARS coronavirus S protein with diagnostic and therapeutic potential. Lu, W., Wu, X.D., Shi, M.D., Yang, R.F., He, Y.Y., Bian, C., Shi, T.L., Yang, S., Zhu, X.L., Jiang, W.H., Li, Y.X., Yan, L.C., Ji, Y.Y., Lin, Y., Lin, G.M., Tian, L., Wang, J., Wang, H.X., Xie, Y.H., Pei, G., Wu, J.R., Sun, B. FEBS Lett. (2005) [Pubmed]
  26. Crystal structure of human purine nucleoside phosphorylase complexed with acyclovir. dos Santos, D.M., Canduri, F., Pereira, J.H., Vinicius Bertacine Dias, M., Silva, R.G., Mendes, M.A., Palma, M.S., Basso, L.A., de Azevedo, W.F., Santos, D.S. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  27. Nucleolar and nuclear aberrations in human lox tumor cells following treatment with p120 antisense oligonucleotide ISIS-3466. Perlaky, L., Smetana, K., Busch, R.K., Saijo, Y., Busch, H. Cancer Lett. (1993) [Pubmed]
  28. Rational design of potent human transthyretin amyloid disease inhibitors. Klabunde, T., Petrassi, H.M., Oza, V.B., Raman, P., Kelly, J.W., Sacchettini, J.C. Nat. Struct. Biol. (2000) [Pubmed]
  29. Crystal structure of human type II inosine monophosphate dehydrogenase: implications for ligand binding and drug design. Colby, T.D., Vanderveen, K., Strickler, M.D., Markham, G.D., Goldstein, B.M. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  30. Structures of nitric oxide synthase isoforms complexed with the inhibitor AR-R17477 suggest a rational basis for specificity and inhibitor design. Fedorov, R., Vasan, R., Ghosh, D.K., Schlichting, I. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  31. A trypanothione-dependent glyoxalase I with a prokaryotic ancestry in Leishmania major. Vickers, T.J., Greig, N., Fairlamb, A.H. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  32. Lipid mediator networks in cell signaling: update and impact of cytokines. Serhan, C.N., Haeggström, J.Z., Leslie, C.C. FASEB J. (1996) [Pubmed]
  33. Perforin/granzyme-dependent and independent mechanisms are both important for the development of graft-versus-host disease after murine bone marrow transplantation. Graubert, T.A., DiPersio, J.F., Russell, J.H., Ley, T.J. J. Clin. Invest. (1997) [Pubmed]
  34. In vitro characterization of enzymatic properties and inhibition of the p53R2 subunit of human ribonucleotide reductase. Shao, J., Zhou, B., Zhu, L., Qiu, W., Yuan, Y.C., Xi, B., Yen, Y. Cancer Res. (2004) [Pubmed]
  35. Inhibition of pRb phosphorylation and cell-cycle progression by a 20-residue peptide derived from p16CDKN2/INK4A. Fåhraeus, R., Paramio, J.M., Ball, K.L., Laín, S., Lane, D.P. Curr. Biol. (1996) [Pubmed]
  36. Phosphotyrosyl peptides block Stat3-mediated DNA binding activity, gene regulation, and cell transformation. Turkson, J., Ryan, D., Kim, J.S., Zhang, Y., Chen, Z., Haura, E., Laudano, A., Sebti, S., Hamilton, A.D., Jove, R. J. Biol. Chem. (2001) [Pubmed]
  37. Structural basis for isotype selectivity of the human retinoic acid nuclear receptor. Klaholz, B.P., Mitschler, A., Moras, D. J. Mol. Biol. (2000) [Pubmed]
  38. Tyrosine kinase inhibitors: from rational design to clinical trials. Traxler, P., Bold, G., Buchdunger, E., Caravatti, G., Furet, P., Manley, P., O'Reilly, T., Wood, J., Zimmermann, J. Medicinal research reviews. (2001) [Pubmed]
  39. Aryl ureas represent a new class of anti-trypanosomal agents. Du, X., Hansell, E., Engel, J.C., Caffrey, C.R., Cohen, F.E., McKerrow, J.H. Chem. Biol. (2000) [Pubmed]
  40. Crystal structure at 2.4 A resolution of Borrelia burgdorferi inosine 5'-monophosphate dehydrogenase: evidence of a substrate-induced hinged-lid motion by loop 6. McMillan, F.M., Cahoon, M., White, A., Hedstrom, L., Petsko, G.A., Ringe, D. Biochemistry (2000) [Pubmed]
  41. Surface plasmon resonance thermodynamic and kinetic analysis as a strategic tool in drug design. Distinct ways for phosphopeptides to plug into Src- and Grb2 SH2 domains. de Mol, N.J., Dekker, F.J., Broutin, I., Fischer, M.J., Liskamp, R.M. J. Med. Chem. (2005) [Pubmed]
  42. Structure of Plasmodium falciparum dihydroorotate dehydrogenase with a bound inhibitor. Hurt, D.E., Widom, J., Clardy, J. Acta Crystallogr. D Biol. Crystallogr. (2006) [Pubmed]
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