DFT-aide d infrare d and electronic circular dichroism spectroscopic study of cyclopeptide S-PK6 and the exploration of its antitumor potential by molecular docking

Cyclic peptides have been widely explored as new chemical modalities in drug design, yet the structural study of bioactive cyclic peptides is often difficult due to the irregular constrained structure. In this article, we reported the infrared (IR) and electronic circular dichroism (ECD) spectroscopic study of an isoindolinone-containing analog (S-PK6) of natural antitumor cyclopeptide Phakellistatin 6. The peak positions of various amino acid residues in the IR spectrum of S-PK6 were specified with the aid of DFT-calculations. To establish a feasible and accurate method for simulating the ECD of small cyclic peptides, we performed a comparison of experimental ECD of S-PK6 with the theoretical spectra calculated by different methods, which indicated that the simulation at the TDDFT/CAM-B3LTP/cc-pVDZ level could provide a decent match for the experimental ECD spectrum of cyclopeptide. Motivated by our previous finding that the isoindolinone-containing cyclopeptides could efficiently inhibit the proliferation of HepG2 cells by decreasing the murine double minute2 (MDM2) protein level, we have investigated the possible binding mode between S-PK6 and MDM2 by molecular docking. Finally, molecular docking of S-PK6 with different cancer-related proteins have been performed, which suggested that diverse intramolecular hydrogen bonding networks might be formed in S-PK6 upon binding to different target protein structures, revealing a target-induced conformational adaptation mechanism. This research provides critical insights into the structure of small cyclopeptides and hints towards the design of peptidyl drugs. (c) 2023 Elsevier B.V. All rights reserved.