• Yuehong Li, Ting Liu, Xiaoyan Lai, Huifang Xie, Heng Tang, Shuangchan Wu, and Yongshun Li.
• Department of Critical Care Medicine, Longyan First Affiliated Hospital of Fujian Medical University, Longyan, China.
• Medicine (Baltimore). 2023 Dec 1; 102 (48): e36188e36188.

AbstractCyclophilin D (CypD) is a mitochondrial matrix peptidyl prolidase that regulates the mitochondrial permeability transition pore. Inhibition of CypD was suggested as a therapeutic strategy for acute pancreatitis. Peptide inhibitors emerged as novel binding ligand for blocking receptor activity. In this study, we present our computational approach for designing peptide inhibitors of CypD. The 3-D structure of random peptides were built, and docked into the active center of CypD using Rosetta script integrated FlexPepDock module. The peptide displayed the lowest binding energy against CypD was further selected for virtual iterative mutation based on virtual mutagenesis and molecular docking. Finally, the top 5 peptides with the lowest binding energy was selected for validating their affinity against CypD using inhibitory assay. We showed 4 out of the selected 5 peptides were capable for blocking the activity of CypD, while WACLQ display the strongest affinity against CypD, which reached 0.28 mM. The binding mechanism between WACLQ and CypD was characterized using molecular dynamics simulation. Here, we proved our approach can be a robust method for screening peptide inhibitors.Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.

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