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Human protein farnesyltransferase (FTase) is involved in many essential signal transduction proteins and has been explored as druggable targets of diverse diseases such as cancer and inflammation. Here, we propose a new strategy termed as Peptide Scaffold‐derived Peptidomimetic FTase Inhibitors (PSPFI) to discover peptidomimetic lead molecular entities that can inhibit FTase. The strategy first defines a PSPFI‐oriented peptidomimetic library that contains >30,000 sulfhydryl/thioether‐carrying peptidomimetics, and then employs molecular docking calculation, multiple similarity analysis, structural minimization, and affinity scoring to screen against the library, in order to discover those peptidomimetics that share high similarity with the core binding module (CBM) of FTase Rap2a peptide substrate in 2D‐chemistry, 3D‐conformation, pharmacophore, and nonbonded pattern, as well as exhibit high theoretical affinity to FTase. Totally 56 hit peptidomimetics were identified from the library, from which we manually select 6 structurally diverse, purchasable peptidomimetics to perform FTase assays. Consequently, four are determined as potent FTase inhibitors (IC50 < 1 μM); their inhibitory activity is moderately lower than the sophisticated FTase inhibitor Tipifarnib and considerably higher than the native CBM peptide. These peptidomimetic ligands share similar extended conformation, binding mode, and Zn2+ coordination with Rap2a CBM peptide in FTase active site, but would have a different inhibition mechanism to Tipifarnib.
Human protein farnesyltransferase (FTase) is involved in many essential signal transduction proteins and has been explored as druggable targets of diverse diseases such as cancer and inflammation. Here, we propose a new strategy termed as Peptide Scaffold‐derived Peptidomimetic FTase Inhibitors (PSPFI) to discover peptidomimetic lead molecular entities that can inhibit FTase. The strategy first defines a PSPFI‐oriented peptidomimetic library that contains >30,000 sulfhydryl/thioether‐carrying peptidomimetics, and then employs molecular docking calculation, multiple similarity analysis, structural minimization, and affinity scoring to screen against the library, in order to discover those peptidomimetics that share high similarity with the core binding module (CBM) of FTase Rap2a peptide substrate in 2D‐chemistry, 3D‐conformation, pharmacophore, and nonbonded pattern, as well as exhibit high theoretical affinity to FTase. Totally 56 hit peptidomimetics were identified from the library, from which we manually select 6 structurally diverse, purchasable peptidomimetics to perform FTase assays. Consequently, four are determined as potent FTase inhibitors (IC50 < 1 μM); their inhibitory activity is moderately lower than the sophisticated FTase inhibitor Tipifarnib and considerably higher than the native CBM peptide. These peptidomimetic ligands share similar extended conformation, binding mode, and Zn2+ coordination with Rap2a CBM peptide in FTase active site, but would have a different inhibition mechanism to Tipifarnib.
Quinoa is an excellent source of nutritional and bioactive components. Protein is considered a key nutritional advantage of quinoa grain, and many studies have highlighted the nutritional and physicochemical properties of quinoa protein. in addition, quinoa protein is a good precursor of bioactive peptides. This review focused on the biological properties of quinoa protein hydrolysate and peptides, and gave a summary of the preparation and functional test of quinoa protein hydrolysate and peptides. A combination of milling fractionation and solvent extraction is recommended for the efficient production of quinoa protein. The biological functionalities of quinoa protein hydrolysate, including antidiabetic, antihypertensive, anti-inflammatory, antioxidant activities, and so on, have been extensively investigated based on in vitro studies and limited animal models. Additionally, bioinformatics analysis, including proteolysis simulation, virtual screening, and molecular docking, provides an alternative or assistive approach for exploring the potential bioactivity of quinoa protein and peptides. Nevertheless, further research is required for industrial production of bioactive quinoa peptides, verification of health benefits in humans, and mechanism interpretation of observed effects.
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