Computational Opportunities and Challenges in Finding Cyclic Peptide Modulators of Protein–Protein Interactions

Peptide cyclization can improve stability, conformational constraint, and compactness. However, apart from beta-turn structures, which are well incorporated into cyclic peptides (CPs), many primary peptide structures and functions are markedly altered by cyclization. Accordingly, to mimic linear peptide interfaces with cyclic peptides, it can be beneficial to screen combinatorial cyclic peptide libraries. Computational methods have been developed to screen CPs, but face a number of challenges. Here, we review methods to develop in silico computational libraries, and the potential for screening naturally occurring libraries of CPs. The simplest and most rapid computational pharmacophore methods that estimate peptide three-dimensional structures to be screened versus targets are relatively easy to implement, and while the constraint on structure imposed by cyclization makes them more effective than the same approaches with linear peptides, there are a large number of limiting assumptions. In contrast, full molecular dynamics simulations of cyclic peptide structures not only are costly to implement, but also require careful attention to interpretation, so that not only is the computation time rate limiting, but the interpretation time is also rate limiting due to the analysis of the typically complex underlying conformational space of CPs. A challenge for the field of computational cyclic peptide screening is to bridge this gap effectively. Natural compound libraries of short cyclic peptides, and short cyclized regions of proteins, encoded in the genomes of many organisms present a potential treasure trove of novel functionality which may be screened via combined computational and experimental screening approaches.