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

Abstract

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.

Structure‐based ligand design by a build‐up approach and genetic algorithm search in conformational space

“…11,32,33 First, PEP uses a library of residue topologies without any predefined structural information. Hence, the conformational optimization in PEP is not restricted to the discrete space of a library of low energy conformations.…”

PRO_LIGAND: An approach to de novo molecular design. 1. Application to the design of organic molecules

“…Here, we describe the operation of PRO_LIGAND for the design of small organic molecules; peptide design will be the subject of a subsequent paper [37]. A further paper will detail the use of PRO_LIGAND with input data derived from a series of active structures or a 3D QSAR study [38].…”

PRO_LIGAND: An approach to de novo molecular design. 6. Flexible fitting in the design of peptides

“…Structures are then built up, taking care to put favourable chemistries in the correct regions of space. Methods of this type use either real chemical fragments [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] or representative templates [29][30][31][32] as building blocks. Of course, even with these broad categories there is some overlap between *To whom correspondence should be addressed.…”

“…PRO_LIGAND is our in-house facility for automated molecular design [25][26][27][28]36] and forms part of the PRO-METHEUS system for molecular design and simulation. It is essentially a rule-based method and, of the other de novo design methods, is most similar to the program LUDI [13].…”

“…In PRO_LIGAND this problem is alleviated somewhat by storing more than one conformation for such flexible fragments. In a previous paper, we have described how libraries of conformations are employed in the building of peptides [28], presenting as an example the building of plausible peptide structures complementary to the active site of HIV-1 protease. This achievement demonstrated that the rule-based approach was a worthwhile strategy for conformationally flexible peptide molecules which, up to that point, had only been treated using energy-based criteria.…”