Synthesis and Molecular Simulation Studies of Mandelic Acid Peptidomimetic Derivatives as Aminopeptidase N Inhibitors

• Published in: Current computer-aided drug design Vol. 17; no. 5; p. 619
• Main Authors: Chen, Jiawei, Lv, Qiaoli, Tu, Guogang
• Format: Journal Article
• Language: English
• Published: United Arab Emirates 01-01-2021
• Subjects: Binding Sites; CD13 Antigens - metabolism; Mandelic Acids; Molecular Docking Simulation; Peptidomimetics - pharmacology; Protease Inhibitors - pharmacology; Structure-Activity Relationship; peptidomimetics; Enzyme inhibitors; aminopeptidase N; APN inhibitors; molecular simulation; scaffold
• ISSN: 1875-6697
• DOI: 10.2174/1573409916666200703161039

The aminopeptidase N (APN) over-expressed in tumor cells plays a critical role in angiogenesis which makes the development of APN inhibitors an attractive strategy for cancer research.
It is clinically significant to develop potential APN inhibitors for cancer treatment. The design, synthesis, biological evaluation and molecular simulation of mandelic acid peptidomimetic derivatives as APN inhibitors are reported.
Analysis of the binding mode of bestatin to APN led to the design and synthesis of mandelic acid peptidomimetic derivatives. APN inhibitory activities in vitro were evaluated by the spectrophotometric method. The binding mode of the target compounds with the APN binding site was studied relying on docking studies, molecular dynamics simulation experiments and binding energies calculation.
The structures of target compounds were confirmed by IR, 1H-NMR and MS. All compounds exhibited a different range of inhibitory ability with IC50 values lying in the micromolar level. The compound 9m was found to be most potent as compared to other target derivatives. The molecular simulation revealed that ligand coordinating with the catalytic zinc ion is very important for inhibitory activities.
The compound 9m might represent a promising scaffold for the further development of novel anti-cancer drugs.