Pharmacy World and Science

, Volume 18, Issue 2, pp 56–62 | Cite as

The role of structure-based ligand design and molecular modelling in drug discovery

  • J. P. Tollenaere


Structure-based ligand design is a technique that is used in the initial stages of a drug development programme. The role of various computational methods in the characterization of the chemical properties and behaviour of molecular systems is discussed. The determination of the three-dimensional properties of small molecules and macromolecular receptor structures is a core activity in the efforts towards a better understanding of structure-activity relationships.


Computer graphics Databases Drug design Molecular conformation Nuclear magnetic resonance Receptors Structure-activity relationship X-ray diffraction 


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  1. 1.
    Fujita T. The extrathermodynamic approach to drug design. In: Hansch C, Sammes PG, Taylor JB, Ramdsen CA, editors. Comprehensive medicinal chemistry. vol. 4. Quantitative drug design. Oxford: Pergamon, 1990: 497–560.Google Scholar
  2. 2.
    Rekker R. The hydrophobic fragmental constant. Amsterdam: Elsevier Scientific Publishing, 1977.Google Scholar
  3. 3.
    Leo AJ. Calculating log Poct from structures. Chem Rev 1993;93:1281–1306.Google Scholar
  4. 4.
    Hansch C, Klein T, McClarin J, Langridge R, Cornell NW. A quantitative structure-activity relationship and molecular graphics analysis of hydrophobic effects in the interactions of inhibitors with alcohol dehydrogenase. J Med Chem 1986;29:615–20.Google Scholar
  5. 5.
    Tollenaere JP, Moereels H, Raymaekers LA. Structural aspects of the structure-activity relationships of neuroleptics: principles and methods. In: Ariëns EJ, editor. Drug design. Vol. 10. Oxford: Academic Press, 1980: 71–118.Google Scholar
  6. 6.
    Allen FH, Davies JE. File structures and search strategies for the Cambridge Structural Database. Crystallogr Comput 1988;2:271–89.Google Scholar
  7. 7.
    Bernstein FC, Koetzle TF, Williams GJB, Meyer EF, Brice MD, Rodgers JR, et al. The Protein Data Bank: a computer-based archival file for macromolecular structures. J Mol Biol 1977;112:535–42.Google Scholar
  8. 8.
    Wüthrich K. The development of nuclear magnetic resonance spectroscopy as a technique for protein structure determination. Acc Chem Res 1989;22:36–44.Google Scholar
  9. 9.
    Lee GM, Chen C, Marchner TM, Andersen NH. Does the solid-state structure of endothelin-1 provide insights concerning the solution-state conformational equilibrium? FEBS Lett 1994;355:140–6.Google Scholar
  10. 10.
    Leach AR. A survey of methods for searching the conformational space of small and medium-sized molecules. In: Lipkowitz KB, Boyd DB, editors. Reviews in computational chemistry. Vol. 2. Weinheim: VCH Publishers, 1991:1–55.Google Scholar
  11. 11.
    Howard AE, Kollman PA. An analysis of the current methodologies for conformational searching of complex molecules. J Med Chem 1988;31:1669–75.Google Scholar
  12. 12.
    Wilson SR, Cui W, Moskowitz JM, Schmidt KE. Applications of simulated annealing to the conformational analysis of flexible molecules. J Comput Chem 1991;12:342–9.Google Scholar
  13. 13.
    Nayeem A, Villa J, Scheraga HA. A comparative study of simulated-annealing and Monte Carlo with minimization approaches to the minimum-energy structures of polypeptides: [Met]-enkephalin. J Comput Chem 1991;12:594–605.Google Scholar
  14. 14.
    Zerner MC. Semiempirical molecular orbital methods. In: Lipkowitz KB, Boyd DB, editors. Reviews in computational chemistry. Vol. 2. Weinheim: VCH Publishers, 1991:313–65.Google Scholar
  15. 15.
    Siebel GL, Kollman PA. Molecular mechanics and the modelling of drug structures. In: Hansch C, Sammes PG, Taylor JB, Ramdsen CA, editors. Comprehensive medicinal chemistry. Vol. 4. Quantitative drug design. Oxford: Pergamon, 1990: 125–38.Google Scholar
  16. 16.
    Bowen JP, Allinger NL. Molecular mechanics: The art and science of parametrization. In: Lipkowitz KB, Boyd DB, editors. Reviews in computational chemistry. Vol. 2. Weinheim: VCH Publishers, 1991:81–97.Google Scholar
  17. 17.
    Brooks BR, Bruccoleri ER, Olafson ER, States DJ, Swaminathan S, Karplus M. CHARMm: A program for macromolecular energy minimization and dynamic calculations. J Comput Chem 1983;4:187–217.Google Scholar
  18. 18.
    Weiner SJ, Kollman PA, Case DA, Singh UC, Ghio C, Alagona G, et al. A new fore field for molecular mechanical simulation of nucleic acids and proteins. J Am Chem Soc 1984; 106:765–84.Google Scholar
  19. 19.
    Clark M, Cramer RD III, Van Opdenbosch N. Validation of the general purpose tripos 5.2 force field. J Comput Chem 1989;10:982–1012.Google Scholar
  20. 20.
    Dinur U, Hagler AT. New approaches to empirical force fields. In: Lipkowitz KB, Boyd DB, editors. Reviews in computational chemistry. Vol. 2. Weinheim: VCH Publishers, 1991:99–164.Google Scholar
  21. 21.
    van Gunsteren WF, Berendsen HJC. Computer simulation of molecular dynamics: methodology, applications and perspectives in chemistry. Angew Chem 1990;29:992–1023.Google Scholar
  22. 22.
    Brunger AT, Karplus M. Molecular dynamics simulations with experimental restraints. Acc Chem Res 1991;24:54–61.Google Scholar
  23. 23.
    Sheridan RP, Rushinko A III, Nilakantan R, Venkataraghavan R. Searching for pharmacophores in large coordinate data bases and its use in drug design. Proc Natl Acad Sci USA 1989;86:8165–9.Google Scholar
  24. 24.
    Martin YC, Bures MG, Willet P. Searching databases of three-dimensional structures. In: Lipkowitz KB, Boyd DB, editors. Reviews in computational chemistry. Vol. 2. Weinheim. VCH Publishers, 1991:213–63.Google Scholar
  25. 25.
    Zuckermann RN, Kerr JM, Kent SBH, Moos WH. Efficient method for the preparation of peptoids [oligo(N-substituted glycines)] by submonomer solid-phase synthesis. J Am Chem Soc 1992;114:10646–7.Google Scholar
  26. 26.
    Simon RJ, Kania RS, Zuckermann RN,Huebner VD, Jewell DA, Banville S, et al. Peptoids: a modular approach to drug discovery. Proc Natl Acad Sci USA 1992;89:9367–71.Google Scholar
  27. 27.
    Zuckermann RN, Martin EJ, Spellmeyer DC, Stauber GB, Shoemaker KR, Kerr JM, et al. Discovery of nanomolar ligands for 7-transmembrane G-protein coupled receptors from a diverse (N-substituted) glycine peptoid library. J Med Chem 1994;37:2678–85.Google Scholar
  28. 28.
    Felder ER. The challenge of preparing and testing combinatorial compound libraries in the fast lane, at the front end of drug development. Chimia 1994;48:531–41.Google Scholar
  29. 29.
    Liskamp RMJ. Opportunities for new libraries: unnatural biopolymer and diversomers. Angew Chem Int Ed (Engl) 1994; 33:633–6.Google Scholar
  30. 30.
    Chen JK, Schreiber SL. Kombinatorische Synthese und mehr-dimensionale NMR-Spektroskopie: ein Beitrag zum Verstandnis von Protein-Ligand-Wechselwirkungen. Angew Chem 1995;107:1041–58.Google Scholar
  31. 31.
    Chothia C, Lesk AM. The relation between the divergence of sequence and structure in proteins. EMBO J 1986;5:823–6.Google Scholar
  32. 32.
    Böhm H-J. The computer program LUDI: a new methods for thede novo design of enzyme inhibitors. J Comput-Aided Mol Design 1992;6:61–78.Google Scholar
  33. 33.
    Böhm H-J. The development of a simple empirical scoring function to estimate the binding constant for a protein-ligand complex of known three-dimensional structure. J Comput-Aided Mol Design 1994;8:243–56.Google Scholar
  34. 34.
    Leach AR, Kilvington SR. Automated molecular design: a new fragment-joining algorithm. J Comput-Aided Mol Design 1994;8:283–98.Google Scholar
  35. 35.
    Kollman P. Free energy calculations: applications to chemical and biochemical phenomena. Chem Rev 1993;93:2395–2417.Google Scholar
  36. 36.
    Loew GH, Villar HO, Alkorta I. Strategies for indirect computer-aided drug design. Pharm Res 1993;10:475–86.Google Scholar
  37. 37.
    Lam PYS, Jadhav PK, Eyermann CJ, Hodge CN, Ru Y, Bacheler LT, et al. Rational design of potent, bioavailable, nonpeptide cyclic ureas as HIV protease inhibitors. Science 1994;263:380–4.Google Scholar
  38. 38.
    Colman PM. Structure-based drug design. Curr Opin Struct Biol 1994;4:868–74.Google Scholar

Copyright information

© Kluwer Academic Publishers 1996

Authors and Affiliations

  • J. P. Tollenaere
    • 1
    • 2
  1. 1.Janssen Research FoundationBeerseBelgium
  2. 2.Department of Pharmaceutical Chemistry, Faculty of PharmacyUtrecht UniversityUtrechThe Netherlands

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