Rational drug design: a multidisciplinary approach.

The pharmaceutical industry developed spasmodically and, in its early years, was shaped by several notable events and scientists. Paul Ehrlich, whose studies initiated the field of chemotherapy, was one of the major contributors. From early experiments on the efficacy of the biological stain methylene blue as an anti-malarial, Ehrlich realized that small molecules could be used to treat infections. Further studies identified trypan dyes and arsenical compounds as treatments of trypanosomal infection, and the arsenical compounds were found to be effective against syphilis. Ehrlich's experience of the chemical industry, in particular the chemistry of dyes, led to the realization that synthetic molecules could be medically useful and provided a powerful stimulus to pharmaceutical research.

[1]  John E. Johnson,et al.  Icosahedral RNA virus structure. , 1989, Annual review of biochemistry.

[2]  W. Lipscomb Structure and mechanism in the enzymic activity of carboxypeptidase A and relations to chemical sequence , 1970 .

[3]  G. Hitchings Selective Inhibitors of Dihydrofolate Reductase (Nobel Lecture) , 1989 .

[4]  G. Elion,et al.  The purine path to chemotherapy , 1989 .

[5]  F. Allen,et al.  The Cambridge Crystallographic Data Centre: computer-based search, retrieval, analysis and display of information , 1979 .

[6]  N. Borkakoti,et al.  Structure of the catalytic domain of human fibroblast collagenase complexed with an inhibitor , 1994, Nature Structural Biology.

[7]  I. Kuntz,et al.  Structure-Based Molecular Design , 1994 .

[8]  K. Sharp,et al.  Protein folding and association: Insights from the interfacial and thermodynamic properties of hydrocarbons , 1991, Proteins.

[9]  Barry Werth,et al.  The Billion Dollar Molecule: One Company's Quest for the Perfect Drug , 1994 .

[10]  G. Elion,et al.  The Purine Path to Chemotherapy (Nobel Lecture) , 1989 .

[11]  P. Vagelos,et al.  Are prescription drug prices high? , 1991, Science.

[12]  B. Matthews,et al.  The structure of thermolysin: an electron density map at 2-3 A resolution. , 1972, Journal of molecular biology.

[13]  J. Black Drugs from emasculated hormones: the principle of syntopic antagonism. , 1989, Bioscience reports.

[14]  G J Williams,et al.  The Protein Data Bank: a computer-based archival file for macromolecular structures. , 1977, Journal of molecular biology.

[15]  S. Redshaw,et al.  The design and synthesis of the Angiotensin Converting Enzyme inhibitor Cilazapril and related bicyclic compounds , 1986 .

[16]  P. Kraulis A program to produce both detailed and schematic plots of protein structures , 1991 .

[17]  I. Kuntz,et al.  Structure-based discovery of inhibitors of thymidylate synthase. , 1993, Science.

[18]  T R Miller,et al.  Principles of therapeutics. , 1992, The Veterinary clinics of North America. Equine practice.

[19]  J. Black Drugs from emasculated hormones: The principle of syntopic antagonism , 1989, In vitro cellular & developmental biology : journal of the Tissue Culture Association.

[20]  D. Filman,et al.  Three-dimensional structure of poliovirus at 2.9 A resolution. , 1985, Science.

[21]  S. Billstein How the pharmaceutical industry brings an antibiotic drug to market in the United States , 1994, Antimicrobial Agents and Chemotherapy.

[22]  P. Colman,et al.  Structure-based drug design. , 1994, Current opinion in structural biology.

[23]  J. Bolin,et al.  Crystal structures of Escherichia coli and Lactobacillus casei dihydrofolate reductase refined at 1.7 A resolution. I. General features and binding of methotrexate. , 1982, The Journal of biological chemistry.

[24]  L. Goodman,et al.  The Pharmacological Basis of Therapeutics , 1941 .

[25]  E A Merritt,et al.  Raster3D Version 2.0. A program for photorealistic molecular graphics. , 1994, Acta crystallographica. Section D, Biological crystallography.

[26]  C L Verlinde,et al.  Structure-based drug design: progress, results and challenges. , 1994, Structure.

[27]  O. Kennard,et al.  SINGLE-CRYSTAL X-RAY DIFFRACTION STUDIES OF OLIGONUCLEOTIDES AND OLIGONUCLEOTIDE-DRUG COMPLEXES , 1991 .

[28]  David T. Jones,et al.  Protein superfamilles and domain superfolds , 1994, Nature.