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

Farhadi, Tayebeh; Hashemian, Seyed MohammadReza

The pharmacophore-based screening was used to find the novel Alzheimer's therapeutics as mimetics of neurotrophins. 132 The therapeutic utilization of neurotrophins might be restricted because of several deficiencies such as its reduced central nervous system penetration, decreased stability and potency to enhance neuronal death through interaction with the p75NTR receptor. The mimetism of particular nerve growth factor domains could inhibit neuronal death. Peptidomimetics of the loop 1 and loop 4 domains of nerve growth factor can prevent neuronal death induced by p75NTR-dependent and Trk-related signaling. 132 In another study, a full-computational pharmacophorebased approach assessed the FDA-approved drugs as valuable candidates to inhibit protein-protein interactions. 133 Peptide structures were designated in terms of pharmacophores and searched against the FDA-approved drugs to detect same molecules. The top ranking drug matches contained several nuclear receptor ligands and matched allosterically to the binding site on the target protein. The top ranking drug matches were docked to the peptide-binding site. The majority of the top-ranking matches presented a negative free energy change upon binding that was comparable to the standard peptide. 133 Geometry similarity method Geometry similarity methods create a geometric similarity between non-peptide templates and peptide patches. In a study, the SuperMimic tool was developed to recognize peptide mimetics. 134 In the program, a complex library of peptidomimetics composed of several protein structure libraries has been deposited. Moreover, SuperMimic includes the D-peptides, synthetic components (reported as betaturn or gamma-turn mimetics) and peptidomimetic ligands obtained from the PDB. 134 In the program, the searching process allows scanning a library of small molecules that mimic the tertiary structure of a query peptide followed by scanning of a protein library where a query for small molecule can adopt into the backbone. 28, 134 Sequence-based method Recently, a method has been developed to rank peptide compound matches that are limited to short linear motifs in proteins and compounds with amino acid substituents. 135 The algorithm allows mapping the side chain-like substituents on every compound of a large chemical library. The complete molecule can be signified by a short sequence, and each fragment in the molecule can be represented as a distinct letter abbreviation. 28 A cross-search between the PubChem database (about 5.4 million molecules) and a non-redundant collection of 11,488 peptides obtained from PDB demonstrated that the algorithm can be useful for high-throughput measurements. 28 To recognize a true positive, the method explored identified protein motifs against the National Cancer Institute Developmental Therapeutic Program compound database. 135 In another study, the Similarity of Amino Acid Motifs to Compounds web server was developed to ease screening of identified motif structures against bioactive compound databases. 136 The methodology was reported to be efficient since the compound databases were preprocessed to maximize the accessible data, and the necessary input data was minimal. 136 In Similarity of Amino Acid Motifs to Compounds, motif matching can be full or partial that may decrease or enhance the number of potential mimetics, respectively. Using a novel search algorithm, the web service can perform a fast screening of known or putative motifs ag