Important note: Information in this article was accurate in 1996. The state of the art may have changed since the publication date.
PRO_LIGAND: an approach to de novo molecular design. 6. Flexible fitting in the design of peptides.
J Comput Aided Mol Des. 1995 Oct;9(5):381-95. Unique Identifier : AIDSLINE MED/96159750 Murray CW; Clark DE; Byrne DG; Proteus Molecular Design Ltd., Lyme Green Business Park,; Macclesfield, Cheshire, U.K.
Abstract:
This paper describes the further development of the functionality of our in-house de novo design program, PRO_LIGAND. In particular, attention is focused on the implementation and validation of the 'direct tweak' method for the construction of conformationally flexible molecules, such as peptides, from molecular fragments. This flexible fitting method is compared to the original method based on libraries of prestored conformations for each fragment. It is shown that the directed tweak method produces results of comparable quality, with significant time savings. By removing the need to generate a set of representative conformers for any new library fragment, the flexible fitting method increases the speed and simplicity with which new fragments can be included in a fragment library and also reduces the disk space required for library storage. A further improvement to the molecular construction process within PRO_LIGAND is the inclusion of a constrained minimisation procedure which relaxes fragments onto the design model and can be used to reject highly strained structures during the structure generation phase. This relaxation is shown to be very useful in simple test cases, but restricts diversity for more realistic examples. The advantages and disadvantages of these additions to the PRO_LIGAND methodology are illustrated by three examples: similar design to an alpha helix region of dihydrofolate reductase, complementary design to the active site of HIV-1 protease and similar design to an epitope region of lysozyme.
Keywords: Amino Acids/CHEMISTRY Animal Binding Sites *Computer-Aided Design *Drug Design Epitopes/CHEMISTRY/IMMUNOLOGY Folic Acid Antagonists/CHEMISTRY Human HIV Protease/CHEMISTRY HIV Protease Inhibitors/CHEMISTRY *Models, Molecular Molecular Conformation Molecular Mimicry Muramidase/CHEMISTRY/IMMUNOLOGY Peptides/*CHEMISTRY Protein Conformation Structure-Activity Relationship Tetrahydrofolate Dehydrogenase/CHEMISTRY JOURNAL ARTICLE
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Important note: Information in this article was accurate in 1996. The state of the art may have changed since the publication date.
