Computer-aided design of amino acid-based therapeutics: a review

Farhadi, Tayebeh; Hashemian, Seyed MohammadReza

Peptidomimetics can be categorized as follows: peptide backbone mimetics (Type 1), functional mimetics (Type 2) and topographical mimetics (Type 3). 29 The first generation of peptidomimetics (Type 1) mimics the local topography of amide bond. It includes amide bond isosteres, 30 pyrrolinones 31 or short fragments of secondary structure, such as beta-turns. 32 Such mimetics generally match the peptide backbone atom-for-atom, and comprise chemical groups that also mimic the functionality of the natural side chains of amino acids. A number of prosperous instances of Type 1 peptidomimetics have been reported. 33 The second type of peptidomimetics is described as functional mimetics or Type 2 mimetics, which include small, non-peptide compounds that are able to identify the biologic targets of their parent peptide. 34 At first, they were assumed to be conservative structural analogs of parent peptides. However, using site-directed mutagenesis, their binding sites to biologic targets were investigated. The results indicated that Type 2 peptidomimetics routinely bind to protein sites that are different from those selected by the original peptide. 35 Therefore, Type 2 mimetics maintain the ability to interfere with the peptide-protein interaction process without the necessity to mimic the structure of the natural peptide. 28 Type 3 peptidomimetics reveal the best conception of peptidomimetics. They consist of the necessary chemical groups that act as topographical mimetics and contain novel chemical scaffolds that are unrelated to natural peptides. 36 Here, theoretical and computational techniques to design proteins, peptides and peptidomimetics are reviewed. However, the current review does not deeply highlight the computational aspects of amino acid-based therapeutic design, but only discusses the methods used to design the mentioned therapeutics. Figure 1 summarizes the key concepts presented in this study.