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

Farhadi, Tayebeh; Hashemian, Seyed MohammadReza

pecific peptidases may limit the clinical application of natural peptides. 19 Moreover, the promiscuity of peptides for their receptors emerges from high degrees of conformational flexibility that can cause undesirable side effects. 20 Besides, some properties of therapeutic peptides, such as high molecular mass and low chemical stability, can result in a weak pharmacokinetic profile. Therefore, peptidomimetic design can be a valuable solution to circumvent some of undesirable properties of therapeutic peptides. 21, 22 In the biologic environment, peptidomimetics can mimic the biologic activity of parent peptides with the advantages of improving both pharmacokinetic and pharmacodynamic properties including bioavailability, selectivity, efficacy and stability. A wide range of peptidomimetics have been introduced, such as those isolated as natural products, 23 synthesized from novel scaffolds, 24 designed based on X-ray crystallographic data 25 and predicted to mimic the biologic manner of natural peptides. 26 Using hierarchical strategies, it is possible to change a peptide into mimic derivatives with lower undesirable properties of the origin peptide. 27 Over the past 10 years, computational methods have been developed to discover peptidomimetics. 28 In a part of this review, novel computational methods introduced for peptidomimetic design have been summarized.