SuperMimic--fitting peptide mimetics into protein structures

Abstract

Background: Various experimental techniques yield peptides that are biologically active but have unfavourable pharmacological properties. The design of structurally similar organic compounds, i.e. peptide mimetics, is a challenging field in medicinal chemistry.

Results: SuperMimic identifies compounds that mimic parts of a protein, or positions in proteins that are suitable for inserting mimetics. The application provides libraries that contain peptidomimetic building blocks on the one hand and protein structures on the other. The search for promising peptidomimetic linkers for a given peptide is based on the superposition of the peptide with several conformers of the mimetic. New synthetic elements or proteins can be imported and used for searching.

Conclusion: We present a graphical user interface for finding peptide mimetics that can be inserted into a protein or for fitting small molecules into a protein. Using SuperMimic, promising locations in proteins for the insertion of mimetics can be found quickly and conveniently.

Figure 1

Geometric values that are evaluated and compared during the primary search. Atoms N^(N) and C_α^(N) are part of the first replaced amino acid; C_α^(C) and C^(C) are part of the last replaced amino acid on the protein side and are the corresponding atoms on the mimetic side. The x-y plane of the coordinate system is defined by the points N^(N), C_α^(N) and C_α^(C), where the x-axis connects N^(N) and C_α^(N). The main characteristic values are the distances x and y. Further characteristic values are β, the angle included by the lines connecting the atoms C_α^(N) and C_α^(C) and also C_α^(C) and C^(C), and γ, the dihedral angle between the N^(N) - C_α^(N) - C_α^(C) and C_α^(N) - C_α^(C) -C^(C) planes.

Figure 2

Screenshots of the SuperMimic program. A. Screenshot of the libraries of peptide mimetics, showing the family of beta-turn-mimetics. Searches can be performed within all conformations of one structure, within a family of mimetics, or within the whole library of mimetics. B. Screenshot after a search for suitable positions of a beta-turn-mimetic within the internal library of about 10403 PDB chains. The picture shows an apoptosis 1 inhibitor from Drosophila melanogaster, PDB-code 1q4q, chain H (yellow), with amino acids 257 and 258 replaced by the mimetic (green).