PRO_LIGAND: an approach to de novo molecular design. 4. Application to the design of peptides

In some instances, peptides can play an important role in the discovery of lead compounds. This paper describes the peptide design facility of the de novo drug design package, PRO_LIGAND. The package provides a unified framework for the design of peptides that are similar or complementary to a speci...

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Bibliographic Details
Published in:Journal of computer-aided molecular design 1995-06, Vol.9 (3), p.213-225
Main Authors: Frenkel, D, Clark, D E, Li, J, Murray, C W, RObson, B, Waszkowycz, B, Westhead, D R
Format: Article
Language:English
Subjects:
AIDS/HIV
Amino Acid Sequence
Binding Sites
Drug Design
Epitopes - chemistry
Epitopes - genetics
HIV Protease - chemistry
HIV Protease Inhibitors - chemistry
HIV-1 - drug effects
HIV-1 - enzymology
Models, Molecular
Molecular Sequence Data
Muramidase - chemistry
Muramidase - genetics
Muramidase - immunology
Peptides - chemistry
Protein Conformation
Software
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Summary:In some instances, peptides can play an important role in the discovery of lead compounds. This paper describes the peptide design facility of the de novo drug design package, PRO_LIGAND. The package provides a unified framework for the design of peptides that are similar or complementary to a specified target. The approach uses single amino acid residues, selected from preconstructed libraries of different residues and conformations, and places them on top of predefined target interaction sites. This approach is a well-tested methodology for the design of organics but has not been used for peptides before. Peptides represent a difficulty because of their great conformational flexibility and a study of the advantages and disadvantages of this simple approach is an important step in the development of design tools. After a description of our general approach, a more detailed discussion of its adaptation to peptides is given. The method is then applied to the design of peptide-based inhibitors to HIV-1 protease and the design of structural mimics of the surface region of lysozyme. The results are encouraging and point the way towards further development of interaction site-based approaches for peptide design.
ISSN:0920-654X
1573-4951
DOI:10.1007/BF00124453