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Document several PTP1B residues at the surface proximate to the well-defined pTyr binding pocket. Such 3D structural information provides insight for the design of peptidomimetic inhibitors of PTP1B. Page 619 In the case of the IRS-1 PTB domain, x-ray crystallographic studies of PTB complexed with a pTyrcontaining peptide (134) complex have shown (Figure 32) that the phosphopeptide forms a type-I β-turn within the Asn-Pro-Ala-pTyr sequence, and the peptide backbone is extensively hydrogen bonded to the PTB domain from the P +1-P -7 residues of 134 [261]. The pTyr binding pocket provides both electrostatic and multiple hydrogen bonding contacts to the phosphate ester moiety, and hydrophobic interactions exist for the P -1-P -3 side chains of the peptide. As in the case of PTP1B, such 3D structural information provides the opportunity for structure-based drug design to discover potent inhibitors which may be used for further exploration in cellular studies. V. Future Perspectives The impact of structure-based drug design on both peptidomimetic and nonpeptide drug discovery has been significant over the past few years. The integration of sophisticated computational chemical technologies, structural biology (x-ray crystallography and NMR spectroscopy), molecular diversity and high-through-put screening, and targeted biological testing are expected to provide invaluable guidance to drug discovery. These “technological tools” are contributing to an emerging “3D structure-activity database” that is the essence of rational drug design. Certainly, this intriguing area of peptidomimetic and nonpeptide drug discovery and design is providing tremendous insight to our understanding of molecular recognition and biochemical mechanisms. With particular regard to molecular diversity, the generation of new leads from combinatorial chemistry focused on synthetic peptide, peptidomimetic, or nonpeptide-type libraries will provide new opportunities (and challenges) for structure-based drug design strategies (for reviews see Reference 276). Novel scaffolds and templates will continue to be advanced and iteratively modified using “randomized” or “targeted” substructural replacements, and such work is exemplified in this review. Of particular significance to the field of peptidomimetic and nonpeptide drug discovery will be the rational use of D-amino acids, Nα-alkyl or Cα-alkyl amino acids, N-substituted Gly, XxxΨ[Z]Yyy (dipeptide isosteres), benzodiazepines, and amino-benzoic acids in structure-based drug design. Without question, structure-based drug design will be a decisive factor in drug discovery efforts ranging from de novo design to iterative structural optimization of peptidomimetic and nonpeptide lead compounds. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_619.html [4/9/2004 1:43:17 AM]
Document Acknowledgments Page 620 I wish to acknowledge my colleagues at Parke-Davis for their critical review of this manuscript as well as for their collaborative contributions to structure-based drug design research in the several areas, including HIV protease inhibitor discovery, Ras farnesyl transferase inhibitor discovery, Src homology- 2 domain antagonist discovery, interleukin-converting enzyme inhibitor discovery, and melanocortin receptor modeling development to probe MSH agonist and antagonists binding. I especially thank Mark Plummer, Elizabeth Lunney, Charles Stankovic, Kim Para, Aurash Shahripour, Vara Prasad, Carrie Haskell-Luevano, Daniel Ortwine, Daniele Leonard, Wayne Cody, and Christine Humblet in this regard. I also very much thank Pandi Veerapandian for the opportunity to contribute a chapter to this book, and for his critical review of this manuscript and excellent editorial suggestions. References 1. (a) Hruby VJ, Al-Obeidi F, Kazmierski W, Biochem J 1990; 268:249–262; (b) Hruby VJ, Pettit BM. In: Perun TJ, Propst CL, Eds. Computer-Aided drug design, Method and Application. New York: Marcel Dekker, 1989:405–461. 2. Fauchere, J-L In: Advances in Drug Research. Vol. 15. Testa B Ed. London: Academic Press, 1986:29–69. 3. Ward DJ. Peptide Pharmaceuticals-Approaches to the Design of Novel Drugs. Buckingham, England: Open University Press, (1991). 5. Toniolo C. Int J Peptide Protein Res 1990; 35:287–300. 4. DeGrado WF. Adv Protein Chem 1988; 39:51–124. 6. Goodman M, Ro S. In: Medical Chemistry and Drug Design. Vol. I. Principles of Drug Discovery. 5th ed. Wolff ME, Ed. 1994:803–861. 7. Kessler H, Haupt A, Will M, In: Computer-Aided Drug Design, Method and Application (Perun TJ, Propst CL, Eds. New York: Marcel Dekker, 1989:461–484. 8. (a) Marshall GR. Tetrahedron 1993; 49:3547–3558; (b) Humblet C, Marshall GR. Ann Report Med Chem 1980; 267–276. 9. Kahn M. Tetrahedron Symposium-In-Print Peptide Secondary Structure Mimetics. 1993:50. 10. McDowell RS, Artis DR. Ann Rep Med Chem 1995; 30:265–274. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_620.html (1 of 2) [4/9/2004 1:43:44 AM]
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