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

Farhadi, Tayebeh; Hashemian, Seyed MohammadReza

For example, in a report, pharmacophore model directed synthesis of the non-peptide analogs of a cationic antimicrobial peptide identified an anti-staphylococcal activity. 129 To make a pharmacophore hypothesis, a model of RNA III-inhibiting peptide (RIP), a well-known heptapeptide inhibitor of the staphylococcal pathogenesis, was utilized. Through the virtual screening of 300,000 commercially available small molecules based on the RIP-based pharmacophore, Hamamelitannin was discovered as a non-peptide mimetic of RIP. Hamamelitannin is a tannin derivate extracted from Hamamelis virginiana. 28, 129 In another study, two rounds of in silico screening were performed to discover potential peptidomimetics able to mimic a cyclic peptide (cyclo- [CPFVKTQLC] ) that is known to bind the anb3 integrin receptor. 130 At the end of the process, the most potent representatives were at least 2,000 times better than the original cyclopeptide (around 2 mM). 130 In a prosperous instance, virtual screening was done by using multi-conformational forms of a large commercial library. A target-based pharmacophoric model mapped the CD4-binding site on HIV-1 gp120. The pharmacophore hypothesis was made based on a homology model of the protein cavity. In a cell-based assay, two of the top scoring molecules were detected as micromolar inhibitors of HIV-1 replication. 131