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Molecular biological techniques make an impact on medicinal chemistry
7’iPS - December
The rapid development of molecular biological techniques for the detection and sequence analysis of genes that encode enzymes or receptors, and for the cloning, and mutagenesis site-specific expression of their cDNAs in a cellular context, has a strong impact on all aspects of medicinal chemistry. At a recent international meeting on trends in drug research*, E. J. Ar’!ns (Nijmegen) stressed that the original receptor concept requires fundamental adaptation, with the focus of structun+activity studies shifting from the ligand to the receptor. The development of molecular biology is not the only reason for this shift of interest. H. Kessler (Munich Technical University) discussed the design of biologically active peptides that have a controlled conformation. This is important because, even with modem NMR spectroscopic techniques, X-ray structure determination and molecular dynamics calculations, the information that can be extracted from studies with flexible ligands is limited. Thus large series of rigid analogues have to be synthesized and tested to define the structural requirements for high biological activity. Although cyclic peptide derivatives that are several orders of magnitude more potent than their natural precursors have been found, it is still not by simple, rational design. But rational design is becoming possible. K. Miiller (HoffmannLaRoche, Basel) described an example that illustrates the methods used today. Refined X-ray crystallographic structure determinations of two bacterial dihydrofolate reductases have been reported’ but until recently the three-dimensional structure of the human reductasr has remained elusive. In Miiller’s laboratory the gene for the human enzyme has now been cloned and expressed. ‘7th Noordwijkerhowt-Camerino Symposium on Trends in Drag Research, Noordwijkerhout, Netherlands, 58 September 1989.
The expressed enzyme has been crystallized and its three-dimensional structure determined. The structures of the human and bacterial reductases are superficially similar, but a detailed analysis revealed small differences in an accessory binding site of these enzymes; this has allowed the successful design of selective inhibitors. Miiller also stressed, however, that the chemist does not have to wait for all this sophisticated information to become available. Formation of a complex with zinc can fold some peptide chains into a finger-shaped conformation and the ‘zinc fingers’ are believed to be essential for recognition of specific DNA sequences. The zinc is either coordinated by two cysteine and two histidine ligands or by four cysteine ligands. Simplified, highly functional modelling methods had been used to suggest the conformation of the peptide chain around the zinc in a complex of the first type. (In fact a paper which was published only two weeks before the meeti& confirmed the structure proposed.) Using the complex with the four cysteine ligands as an example, Miiller demonstrated that many possible conformations of such a complex could be generated by searching available structural databases combined with the use of modelling tools. These predictions can then serve as the basis for further studies. One of the topics of a lecture by G. Beck (Hoechst, Frankfurt) on new inhibitors of hydroxymethylglutaryl-CoA reductase was a discussion of the challenge for the chemist to develop cost-effective, scalable and robust syntheses for such complex chiral molecules. A number of synthetic routes either starting from chiral natural products ar using enantioselective reactions were e .@ored. This trend towards more complex chiral drugs is a general one. The disadvantages of racemic drugs and even more of diastereomerit mixtures are now generally recognized3 and the synthesis has
2989 [Vol. 101
to be directed to the biologically enantiomer or isomer. active organic Interesting synthetic reactions have been reported but these often require very low temperatures (which are expensive to maintain) and/or toxic engineering reagents. Genetic may open up interesting alternative approaches. H. J. Kooreman (IBIS, Rijswijk) illustrated this with the successful synthesis of the s-enantiomer of the antiinflammatory drug naproxen, which is based upon the enantioselective hydrolysis, by a microbial enzyme, of alkylesters of the racemic drug. This enzyme, synthesized using the cloned gene, allows both the level of production and the enantiomeric purity of the drug to be greatly improved4. F. J. ZEELEN Floraliasfr.
2, 5384 GP Heesch, Netherlands.
Proceedings of this conference, which covered a number of other topics, are to be published by Elsevier in early 1990. References 1 Matthews, D. A.
et al. (1978) 1. Biol. Chem.
253.6946-6954
2 Lee; M. S. et al. (1989) Science 245, 635-637 3 Simonyi, M., Gal, J. and Testa, 8. (1989) Trends Phannacol. Sci. 10, 349-354 4 Quax, W. J. et al. (1987) in Proceedings of the 4th European Congress on Biotechnology (Vol. 1) (Neijssel, 0. M., van der
Mew, R. R. and Luyben, eds), p. 519, Elsevier
K. Ct. A. M.,
British Scientists Abroad British Scientists Abrcad have launched a petition to draw attention to the effect of UK government science funding policies in driving academics abroad. The petition is to be signed only by British scientists working overseas, and is desicxxd to illustrate the brain drain’ ir, teIlIls of names, LIKdegrees %ld current positions held. For rqy of petition, write (SAE appreciated) or call: British sr!tintlsts Abroad (BSA), c/o Dr Marie Rose Schravendijk, Latxxatory of Infectious Diseases, DNAH Research Institute, 901 Cahfomia Avenue, Palo Alto, CA 94304-l104, USA. Tel: (1)415 856 4214.
The rapid development of molecular biological techniques for the detection and sequence analysis of genes that encode enzymes or receptors, and for the cloning, and mutagenesis site-specific expression of their cDNAs in a cellular context, has a strong impact on all aspects of medicinal chemistry. At a recent international meeting on trends in drug research*, E. J. Ar’!ns (Nijmegen) stressed that the original receptor concept requires fundamental adaptation, with the focus of structun+activity studies shifting from the ligand to the receptor. The development of molecular biology is not the only reason for this shift of interest. H. Kessler (Munich Technical University) discussed the design of biologically active peptides that have a controlled conformation. This is important because, even with modem NMR spectroscopic techniques, X-ray structure determination and molecular dynamics calculations, the information that can be extracted from studies with flexible ligands is limited. Thus large series of rigid analogues have to be synthesized and tested to define the structural requirements for high biological activity. Although cyclic peptide derivatives that are several orders of magnitude more potent than their natural precursors have been found, it is still not by simple, rational design. But rational design is becoming possible. K. Miiller (HoffmannLaRoche, Basel) described an example that illustrates the methods used today. Refined X-ray crystallographic structure determinations of two bacterial dihydrofolate reductases have been reported’ but until recently the three-dimensional structure of the human reductasr has remained elusive. In Miiller’s laboratory the gene for the human enzyme has now been cloned and expressed. ‘7th Noordwijkerhowt-Camerino Symposium on Trends in Drag Research, Noordwijkerhout, Netherlands, 58 September 1989.
The expressed enzyme has been crystallized and its three-dimensional structure determined. The structures of the human and bacterial reductases are superficially similar, but a detailed analysis revealed small differences in an accessory binding site of these enzymes; this has allowed the successful design of selective inhibitors. Miiller also stressed, however, that the chemist does not have to wait for all this sophisticated information to become available. Formation of a complex with zinc can fold some peptide chains into a finger-shaped conformation and the ‘zinc fingers’ are believed to be essential for recognition of specific DNA sequences. The zinc is either coordinated by two cysteine and two histidine ligands or by four cysteine ligands. Simplified, highly functional modelling methods had been used to suggest the conformation of the peptide chain around the zinc in a complex of the first type. (In fact a paper which was published only two weeks before the meeti& confirmed the structure proposed.) Using the complex with the four cysteine ligands as an example, Miiller demonstrated that many possible conformations of such a complex could be generated by searching available structural databases combined with the use of modelling tools. These predictions can then serve as the basis for further studies. One of the topics of a lecture by G. Beck (Hoechst, Frankfurt) on new inhibitors of hydroxymethylglutaryl-CoA reductase was a discussion of the challenge for the chemist to develop cost-effective, scalable and robust syntheses for such complex chiral molecules. A number of synthetic routes either starting from chiral natural products ar using enantioselective reactions were e .@ored. This trend towards more complex chiral drugs is a general one. The disadvantages of racemic drugs and even more of diastereomerit mixtures are now generally recognized3 and the synthesis has
2989 [Vol. 101
to be directed to the biologically enantiomer or isomer. active organic Interesting synthetic reactions have been reported but these often require very low temperatures (which are expensive to maintain) and/or toxic engineering reagents. Genetic may open up interesting alternative approaches. H. J. Kooreman (IBIS, Rijswijk) illustrated this with the successful synthesis of the s-enantiomer of the antiinflammatory drug naproxen, which is based upon the enantioselective hydrolysis, by a microbial enzyme, of alkylesters of the racemic drug. This enzyme, synthesized using the cloned gene, allows both the level of production and the enantiomeric purity of the drug to be greatly improved4. F. J. ZEELEN Floraliasfr.
2, 5384 GP Heesch, Netherlands.
Proceedings of this conference, which covered a number of other topics, are to be published by Elsevier in early 1990. References 1 Matthews, D. A.
et al. (1978) 1. Biol. Chem.
253.6946-6954
2 Lee; M. S. et al. (1989) Science 245, 635-637 3 Simonyi, M., Gal, J. and Testa, 8. (1989) Trends Phannacol. Sci. 10, 349-354 4 Quax, W. J. et al. (1987) in Proceedings of the 4th European Congress on Biotechnology (Vol. 1) (Neijssel, 0. M., van der
Mew, R. R. and Luyben, eds), p. 519, Elsevier
K. Ct. A. M.,
British Scientists Abroad British Scientists Abrcad have launched a petition to draw attention to the effect of UK government science funding policies in driving academics abroad. The petition is to be signed only by British scientists working overseas, and is desicxxd to illustrate the brain drain’ ir, teIlIls of names, LIKdegrees %ld current positions held. For rqy of petition, write (SAE appreciated) or call: British sr!tintlsts Abroad (BSA), c/o Dr Marie Rose Schravendijk, Latxxatory of Infectious Diseases, DNAH Research Institute, 901 Cahfomia Avenue, Palo Alto, CA 94304-l104, USA. Tel: (1)415 856 4214.